Chapter 55
Molecular Genetic Basis of Eye Diseases
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Supported in part by the Henry and Corinne Bower Laboratory, Philadelphia, PA.


In the last 10 years, we have seen an explosion of knowledge in the understanding of molecular mechanisms of disease processes as a result of cloning of a number of important disease-causing genes, such as those for cystic fibrosis,1 familial breast and ovarian cancer,2,3 colon cancer,4 Huntington's disease,5 Alzheimer's disease, and obesity.6 Because vision is such an important sense, and since many genetic abnormalities that affect visual function can be detected, research on the molecular basis of ophthalmic diseases has grown tremendously in recent years. In fact, many important discoveries in molecular ophthalmology have played critical roles in the development of entirely new fields in molecular genetics. For example, the identification and cloning of the retinoblastoma gene (RB1) has served as the prototype of an important new class of cancer-causing genes: the tumor-suppressor genes. In retinitis pigmentosa, DNA point mutations have been identified, serving as the first example of retinal degeneration caused by DNA alterations in photoreceptor proteins. In many ways, the study of the molecular basis of ocular diseases has led to many exciting new discoveries in the molecular biology of human diseases in general.

Faced with these rapid new developments in molecular ophthalmology, it is becoming imperative that ophthalmologists who are involved in the day-to-day care of patients keep abreast of the major scientific advances in the field and that they recognize new diagnostic and therapeutic modalities. As of 1996, many hereditary ophthalmic diseases have been examined in detail through the use of molecular genetic techniques. In many instances, the actual disease genes have been identified and mutations characterized in patients. This chapter provides a review of the basic principles of molecular genetics as applied to ophthalmology as well as a discussion of the current understanding of molecular pathogenic mechanisms of many important ocular diseases. Clinical applications are described, including DNA diagnosis, genetic counseling, and treatment. In an attempt to help ophthalmologists grasp the essential features of these exciting new scientific developments, the chapter places emphasis on the correlation between laboratory findings and clinical disease entities. Excellent reviews of this field can also be found elsewhere.7–25

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Many of the 3000 known hereditary disorders that affect humans have ocular manifestations.26 These diseases can be transmitted according to various modes of genetic transmission, including autosomal dominant, autosomal recessive, X-linked dominant (rare) or recessive, multifactorial inheritance, and cytoplasmic inheritance.

The most common mode of transmission for ocular diseases is autosomal-dominant transmission. Examples of ocular diseases with autosomaldominant traits include aniridia, Best's disease, corneal dystrophies, retinoblastoma, and neurofibromatosis. For an inherited disorder to be classified as autosomal dominant, it must meet four general criteria27:

  1. Affected members appear in every generation, each patient having an affected parent.
  2. Any child of an affected parent has a 50% risk of inheriting the trait.
  3. Phenotypically normal family members do not transmit the phenotype to their children.
  4. Males and females are equally likely to transmit the phenotype to children of either sex.

Exceptions to these rules, however, do exist. For example, an autosomal-dominant disorder may have a reduced penetrance, which is defined as the percentage of persons with a given genotype who are affected. Studies of low-penetrant disorders have provided insight into the molecular pathogenicity of various DNA mutations, as demonstrated in the case of retinoblastoma.28–31

The criteria for a disorder to be classified as autosomal recessive are as follows27:

  1. It appears in more than one member of a kindred and typically is seen only in the sibship of the proband, not in parents or offspring.
  2. The recurrence risk for each sibling of the proband is 25%.
  3. The parents of the affected person often are consanguineous.
  4. Males and females are equally likely to be affected. Autosomal-recessive disorders in ophthalmology include gyrate atrophy, Stargardt's disease, Tay-Sachs disease, and Usher's syndrome.

X-linked recessive disorders are the most common of the X-linked disorders. Examples of X-linked recessive disorders in the eye include choroideremia, ocular albinism, red-green color blindness, and Fabry's disease. X-linked recessive disorders are characterized by the following five criteria27:

  1. The incidence of the trait is much higher in males than in females.
  2. The disease gene is transmitted from an affected man through all of his daughters. Any of his daughters' sons has a 50% chance of inheriting the disease gene.
  3. The gene is never transmitted directly from father to son.
  4. The gene may be transmitted through carrier females.
  5. Heterozygous females are usually unaffected, but some may express the condition with variable severity.

Other modes of genetic transmission include multifactorial inheritance and cytoplasmic inheritance. Multifactorial inheritance is characterized by the presence of a significant environmental influence. Many ophthalmic diseases such as age-related macular degeneration and primary open-angle glaucoma may eventually prove to be in this category. Examples of cytoplasmic inheritance include mitochondrial disorders, such as Leber's hereditary optic neuropathy and Kearn-Sayre syndrome. These traits are characterized by a maternal transmission pattern.


The physical basis of a gene is the DNA molecule. Since the demonstration of the DNA structure in 1953 by James Watson and Francis Crick, the DNA molecule has become the cornerstone of molecular biology. A DNA molecule consists of four basic building blocks: adenine (A), guanine (G), cytosine (C), and thymine (T). The remarkable precision by which A is paired only with T, and G only with C ensures genetic reproducibility. In the nucleus of a cell, the DNA molecule is transcribed into a RNA molecule, which differs from DNA in that RNA is single-stranded and contains uracil (U) instead of thymine (T). The messenger RNA (mRNA) molecule is then translated into a protein molecule on ribosomes in the cytoplasm, completing the process of gene expression. Alterations at the level of DNA can be minute (as in point mutation of a base) or more extensive (as in a deletion of a large segment of DNA). These DNA alterations can result in the production of abnormal RNA molecules, leading to protein abnormalities and human diseases.


The Human Genome Project, which will provide a detailed physical map of all of the human chromosomes, should be completed by the year 2000.26,32 In recent years, the Human Genome Project has made remarkable progress, mainly due to the development of new cloning and sequencing strategies, such as yeast artificial chromosomes and microsatellite repeat markers.32,33 The availability of a human gene map will provide molecular biologists with a road map that not only will greatly facilitate the search for disease-causing genes, but also will make possible rational design of genetic diagnosis and therapy.


In the following sections, essential features of major experimental tools used in molecular biology will be described, particularly with regard to studies of genes related to vision.

Polymerase Chain Reaction

Invented in 1988,34 the polymerase chain reaction (PCR) has revolutionized molecular biology, particularly with regard to gene amplification and cloning. The goal of PCR is to amplify a DNA fragment of interest in sufficient quantity for molecular biologic analysis. In a typical PCR reaction, the parent DNA fragment is bound by two primers—short stretches of DNA molecules with sequences complementary to either terminus of the parent DNA fragment. A thermally stable DNA polymerase is then added, and the reaction mixture undergoes a series of repeated thermal cycles. The number of copies of the product DNA fragments will then be amplified to 2n, where n is the number of amplification cycles. PCR can typically amplify DNA fragments up to 1 kilobase (kb) in size. To amplify larger DNA fragments, one has to resort to gene cloning using vectors.

Gene Cloning Using Vectors

Cloning of large gene fragments requires the use of a vector. A vector is typically a circular, double-stranded DNA molecule such as a bacterial plasmid. Using restriction endonuclease enzymes, a target DNA fragment of interest is inserted into the circular DNA structure of a plasmid vector, thus creating a recombinant DNA clone. The clone is then transformed into a host bacterial cell and is amplified along with the cell divisional process of the host. Finally, multiple copies of the original recombinant clone are then isolated from the host bacteria cells. The goal of the entire cloning process is to amplify the original gene fragment for further molecular characterization.

Southern Blot

Invented by Edwin Southern in 1975,35 the Southern blot is used to separate DNA fragments by electrophoresis and then to transfer the fragments onto a solid support. A DNA sample to be analyzed is first digested with a restriction endonuclease, which cuts the DNA at certain specific sequences. These fragments are separated by size with the use of gel electrophoresis. The gel electrophoretic pattern is then transferred onto a solid support, such as nitrocellulose. A DNA probe is then constructed with its sequence complementary to that of the target DNA fragment to be visualized. The DNA probe is radioactively labeled and hybridized with the target DNA fragments immobilized on the nitrocellulose filter. The final electrophoretic pattern of only the DNA fragment of interest (as picked out by the specific DNA probe) is visualized by autoradiography. The power of the Southern blot lies in its ability to characterize the sizes of DNA fragments containing specific sequences. The technique can be used, for example, to detect large deletions or duplications of a gene fragment, as is sometimes found in patients with retinoblastoma.

Restriction Fragment Length Polymorphism

In 1980, Botstein and associates36 discovered that the naturally existing degree of variation in the distribution of restriction enzyme sites found in human chromosomes can be used as landmarks for identifying the chromosomal location of gene segments. This finding, termed restriction fragment length polymorphism (RFLP), has greatly accelerated linkage analysis and the characterization of human genes. In an RFLP analysis, DNA from the patients are cleaved by restriction enzymes, and the resulting DNA fragments are separated by gel electrophoresis. Because each patient has a specific distribution of these restriction enzyme sites, the RFLP pattern is unique to each patient. Currently several hundred restriction enzymes are available for RFLP analysis. The combination of a collection of RFLP markers can often be much more effective in detecting the presence or absence of a specific DNA fragment in a particular person, as demonstrated in the genetic diagnosis of retinoblastoma.30,37

Variable Number of Tandem Repeats

For a DNA marker to be useful in characterizing unique DNA fragments, it should have a large number of polymorphic forms. An RFLP marker often has only two polymorphisms, thus limiting its use in genetic testing. Another class of more powerful DNA markers has since been found: the variable number of tandem repeats (VNTR) marker.38 A VNTR marker consists of a series of allelic fragments that are related to each other by a variable number of repeats of a short stretch of DNA sequence (tandem). VNTR markers are highly polymorphic, making them the most commonly used DNA markers in the characterization of human chromosomal fragments. Several thousand VNTR markers have been identified to date throughout the human genome.39,40

Single-Strand DNA Gel Electrophoresis

This technique is used to detect the presence of DNA mutations in a given gene. A single-stranded gene fragment moves with a specific motility corresponding to its three-dimensional conformation determined by its sequence. If a gene fragment contains mutations, it will have an altered three-dimensional structure and thus a different electrophoretic motility compared with that of a normal gene. This method, termed single-strand conformational polymorphism (SSCP), is used for rapid screening of gene fragments to determine whether mutations are present.41 Figure 1 shows an example of the SSCP technique. Although the technique is efficient for detecting the presence of a mutation, it usually cannot determine the nature of the mutation. The exact alterations in base sequences of the gene fragments can be determined by techniques such as DNA sequencing.

Fig. 1. A diagram demonstrating two molecular detection techniques. Allele-specific hybridization (top) for the detection of point mutations in the rhodopsin gene in patients with autosomal-dominant retinitis pigmentosa. The dark spots represent DNA containing mutations at codon 23 of the rhodopsin gene. Electrophoretic pattern (bottom) demonstrating the nonradioactive single-strand conformational polymorphism technique. The leftmost lane corresponds to a retinoblastoma gene fragment containing a point mutation, resulting in altered motility compared with the rest of lanes with normal DNA. (Adapted from Wang MX, Donoso LA: Gene research and the eye. Curr Opin Ophthalmol 4(III): 102, 1993)

DNA Sequencing

The discovery in 1977 of rapid DNA sequencing technologies by Sanger and colleagues42 and Maxam and Gilbert43 has helped usher in a new era of molecular biology. It became possible to determine the exact composition of genes with the ultimate resolution: the base-to-base DNA sequence. The Sanger method42 uses an ingenious chain-termination technique such that the target DNA fragment to be analyzed is replicated in small fragments that terminate at specific bases. The DNA sequence is then determined by the electrophoretic pattern of these DNA fragments. In contrast, the method used by Maxam and Gilbert43 cleaves the target DNA fragments into small pieces using chemical reagents that cut only at specific bases. The final DNA sequence is read from electrophoretic gel patterns of the cleaved DNA fragments.

Northern Blot

The Northern blot is the counterpart of the Southern blot. It is used to analyze RNA samples. The purpose of the northern blot is to determine the size and abundance of mRNA of a specific gene. RNA from a particular cell type is electrophoretically separated on a gel and transferred onto a solid support. To visualize these mRNA fragments, a DNA probe containing part of the sequence of the gene is constructed. The probe is radioactively labeled and hybridized with the RNA sample immobilized on the solid support. The resulting radioactively labeled target mRNA fragment is then analyzed by autoradiography.

Western Blot

A Western blot is used to analyze proteins. It is a counterpart of the Southern blot (for DNA analysis) and northern blot (for RNA analysis). A protein extract obtained from cells of a patient with a genetic disease is separated by size with the use of polyacrylamide gel electrophoresis. After transferring the protein fragments onto a solid support, radioactively labeled antibodies that specifically bind to the protein of interest are incubated with the protein fragments. The western blot is used to obtain information about the size and abundance of mutant proteins in patients suffering from a genetic disease.


Gene mutations lead to human diseases. A DNA mutation is defined as a permanent change in the sequence of a gene. There are three general categories of DNA mutations27: genome mutations, chromosome mutations, and gene mutations. Genome mutations involve missegregation of a chromosome during cell division, as seen in Down's syndrome (trisomy 21). Genome mutations are the most common type of DNA mutations seen in humans. Chromosome mutation occurs less frequently and involves rearrangement of chromosomes. An example of a chromosomal mutation in ophthalmology is the sporadic form of aniridia involving chromosome 11p deletion. In addition to aniridia, these patients may have a predisposition to Wilms' tumor, genitourinary anomalies, andmental retardation.44–46 Gene mutation is caused by errors in DNA replication or induced mutation by mutagens.

Human DNA replication is highly efficient and accurate. Spontaneous errors in DNA replication occur only about once every 10 million base pairs.27 A wide variety of chemical and environmental mutagens, however, can cause induced gene mutations. Gene mutations can involve deletions and insertions of gene segments, or point mutations that involve a single nucleotide substitution. A point mutation can alter a triple base codon, resulting in a change in an amino acid in a protein product. A single nucleotide substitution can be either a transition mutation, in which one purine is changed to another purine (e.g., A changed to G), or a transversion mutation, in which a purine is replaced by a pyrimidine or vice versa (e.g., A replaced by C, or C by A).

Gene mutation can occur in a variety of forms, including missense mutation, nonsense mutation, or RNA-splicing mutation. A missense mutation is a point mutation in a DNA sequence that alters a triplet code for an amino acid, resulting in the replacement of an amino acid. In autosomaldominant retinitis pigmentosa (ADRP), for example, the first point mutation identified in the rhodopsin gene consists of the replacement of C by A, which results in the change of the amino acid proline to histidine.47 Since proline is important in the three-dimensional structure of rhodopsin, its loss leads to a functional alteration of the protein. Nonsense mutation consists of a DNA point mutation that creates a stop codon in the corresponding mRNA, resulting in the premature termination of the translation of the protein and giving rise to a shortened or truncated protein. Examples in ocular diseases include a nonsense mutation in the rhodopsin gene in patients with autosomal-recessive retinitis pigmentosa48 and premature termination codon identified in patients with Stickler's syndrome (arthro-ophthalmopathy; See Stickler's Syndrome section later in chapter). In RNA splicing mutation, transcription of DNA produces unprocessed RNA, which is subsequently spliced to remove the intron sequences, leaving only exons. DNA point mutations involving bases corresponding to the RNA-splicing region may result in abnormal processing of RNA. An example of an RNA-splicing mutation involving ocular disease can be seen in retinoblastoma. As demonstrated by Horowitz and co-workers,49 a point mutation at the splicing site of exon 21 of RB1 causes the loss of exon 21 in the mRNA product, resulting in a truncated retinoblastoma protein.

The relationship between the types and locations of DNA mutations and the extent of clinical manifestation of human diseases is an active area of research today. Advances in this field not only will improve our understanding of the molecular mechanism of the disease processes, but also will greatly aid in DNA diagnosis and genetic counseling. More than 40 types of RB1 mutations have been identified. Notably, more than one third of these mutations occur in the noncoding region of RB1, grossly altering the RB1 product by affecting processes such as RNA splicing. Among the DNA mutations identified in RB1, there appears to be no “hot spot” (i.e., a point mutation that occurs in a majority of the patients). This is in contrast to other human diseases (e.g., cystic fibrosis), in which a single point mutation accounts for 70% of patients with the disease (a three base pair deletion that removes the phenylalanine at position 508 of the cystic fibrosis gene [CF]).1,50–52 This is particularly relevant in clinical DNA diagnosis and genetic counseling, since the lack of a hot-spot mutation in RB1 makes it necessary to screen and analyze all segments of RB1 in order to identify the causative mutation, a time-consuming and laborious process.


The clinical manifestations of genetic mutations depend on many factors. The following are several key concepts in examining the relationship between genotypes (DNA mutations) and phenotypes (clinical disease).24

  1. Allelic heterogeneity refers to the concept that various mutations in one gene can be associated with different clinical presentations of the disease. For example in the human rhodopsin gene, different mutations are found which are associated with varying clinical severities of ADRP.
  2. Nonallelic heterogeneity (locus heterogeneity) refers to the observation that mutations in several different genes can be associated with various clinical phenotypes of the disease. For example, several gene mutations associated with ADRP have been identified, including mutations of the rhodopsin and human peripherin/RDS genes (located on chromosomes 3q and 6p, respectively).
  3. The concept of expressivity refers to the extent of disease manifested in patients who have the same gene mutation. For example, in some cases of ADRP, family members sharing the same inherited rhodopsin gene mutation show different degrees of the disease.53 Another example is in the case of familial exudative vitreoretinopathy (FEVR). FEVR can be inherited as an autosomal-dominant disease with almost full penetrance. The severity of the disease, however, varies significantly, even among family members in the same pedigrees who have inherited the same gene mutation. Some patients may be found to have minimal disease, discovered only after a more severely affected member of the family is examined.54
  4. Penetrance refers to the percentage of family members in a given pedigree who have inherited the same mutant allele and manifest the disease clinically. In retinoblastoma, it has been noted that certain mutant retinoblastoma alleles have a lower penetrance than that expected from a classic autosomal-dominant transmission.28–31

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There are two main strategies in mapping and identifying disease-causing genes: positional cloning and functional cloning.


In positional cloning and linkage analysis, DNA segments are examined to see whether a set of DNA markers cosegregates with affected persons. The rapid development in the Human Genome Project and the availability of the second- and third-generation human genome markers, with a resolution of 2 centimorgans or less, has rapidly advanced the speed and accuracy of linkage analysis.

In a typical chromosomal linkage study, statistical analysis is performed to determine the probability of cosegregation of the DNA markers with the disease. The closer the chromosomal distance between a DNA marker and a disease gene, the more likely it is that the DNA marker will travel together (cosegregate) with the disease gene in chromosomal recombination events. A score of the logarithm of the odds favoring linkage (LOD score) is used to quantify the distance between the marker and the disease gene. Since the LOD is calculated as the logarithm to base 10 of the odds in favor of linkage, a LOD score of 3 represents a probability of 1000:1 that the observation of linkage did not occur by chance and is often taken as the minimal LOD value for presumptive evidence of linkage. In addition to helping identify the disease gene, these DNA markers (particularly intragenic DNA markers) have also proved useful for clinical genetic diagnosis.11,18,20,30,37,55–61 The above-described strategy of linkage analysis and positional cloning is often termed “reverse genetics.” This is because, in contrast to certain examples in classical genetics such as sickle cell anemia, in which the biochemical defect is known before the chromosomal localization of the genetic defect, in linkage analysis and positional cloning there is no prior knowledge of the nature of the biochemical defect involved in the disease.

Positional cloning typically consists of two general strategies, chromosome walking and chromosome jumping. For example, in the cloning of CF, linkage studies mapped the disease gene locus to chromosome 7q31. Chromosome walking techniques were then used to reveal the finer details in 7q31 region. Chromosome walking involves first creating a library of clones by cleaving the entire genome and cloning these fragments. A DNA marker in the chromosomal region established by linkage analysis is then used to “fish out” a clone in the library that cosegregates with the disease. Once such a clone is identified, it is cleaved into smaller fragments, which are subcloned. One of the subcloned fragments is then regarded as the “first step” in chromosome walking. It is then used as a DNA probe to fish out the next adjacent clone in the library, walking onto the “next step” and thus organizing the clones in a series. This chromosome walking process is repeated until the disease gene is finally encountered. In the case of cystic fibrosis, exhaustive chromosome-walking effort has converged on a DNA segment that might contain CF. The gene tracking effort was then complemented and accelerated by a second technique, chromosome jumping. Chromosome jumping relies on the creation of larger DNA clones and recircularization processes to track down genes. With the combination of chromosome walking and jumping techniques, a DNA segment that appeared to contain CF was finally isolated.1,50–52

The identification of a disease-causing gene must satisfy the following requirements, as demonstrated in cystic fibrosis1:

  1. The putative gene should contain an open reading frame with the proper start and stop regions expected of a gene.
  2. It should contain CG-rich sequences in the 5' upstream region, consistent with a regulatory sequence structure of a gene.
  3. It should be evolutionarily conserved, as demonstrated by “zoo” blot (comparison of a DNA fragment among species).
  4. It must have a transcript (i.e., the corresponding mRNA is present in a cell).

Once a disease gene is identified, verification of its authenticity is important. Again let us discuss cystic fibrosis as an example. The putative CF satisfies the following criteria:

  1. Mutations in the putative CF have indeed been found in patients with the disease.
  2. The protein structure encoded by CF resembles that of a membrane transport protein, consistent with the expectation based on the pathophysiologic abnormality.
  3. Transfection of the intact CF corrects the defect in animal models.

Linkage analysis and positional cloning, although extremely powerful, have limitations. For instance, for a disease with locus heterogeneity such as that shown in many hereditary retinal diseases, linkage data may be susceptible to error, since entirely different gene loci may be deranged in a single disease. This is the case for ADRP, where at least 10 different genetic loci have been identified to date.14,20,24,47,62–75,76–92 In addition, linkage analysis and positional cloning are labor intensive in that they both require extensive analysis of DNA markers. In some instances an alternative strategy, functional cloning, may offer a short cut to uncover the genetic defect.


The second major strategy for localizing disease-causing genes is called functional cloning (or candidate gene approach), in which a gene located in the chromosomal region of interest is chosen for study because it is likely to be related to the disease process. If mutations indeed are found in this candidate gene in patients who have a given disease, the candidate gene is then “elected.” With the rapid accumulation of DNA sequence data from the Human Genome Project, it has become increasingly feasible to make use of the candidate gene approach. Three main guidelines govern the candidate gene approach:

  1. The location of the candidate genes should be consistent with prior linkage studies.
  2. The biologic function of the candidate gene should be logically related to the disease process.
  3. The candidate gene product should be expressed in the tissue examined.

The successful demonstration of the first point mutation in the rhodopsin gene in ADRP47 is an excellent example of the candidate gene approach. It was made possible by a prior study by McWilliam and colleagues,62 who demonstrated segregation of retinitis pigmentosa in a large Irish pedigree to chromosome 3q (i.e., the same chromosomal location as rhodopsin). Examination of the rhodopsin genes in patients with ADRP did reveal causative DNA mutations.47

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In Table 1, we have provided a list of the chromosomal locations of several ocular diseases. In the following sections, we will discuss specific ocular diseases for which progress has been made recently regarding the molecular pathogenesis.


TABLE ONE. Chromosomal Locations of Disease Genes with Ocular Manifestations

Adenomatous polyposis of the colon5q22 - q23
Aicardi syndromeXp22
Aland eye diseaseXp11.4 - q21
Aland eye disease (Forsius-Erikson)Xp21.3 - p21.1
Albinism, ocular, Nettleship-Falls typeXp22.3
Albinism, oculocutaneous 2, tyrosinase-positive2q31.2 or 4q31.22
Albinism oculocutaneous, tyrosinase-negative11q14 - q21
Alport's syndromeXq22 - 24
Aniridia, isolated 12p25
Aniridia, isolated 211p13
WAGR (PAX6, aniridia with Wilms's tumor)11p13
Anophthalmos, X-linkedXq27 - q28
Anterior segment mesenchymal dysgenesis4q23 - 31
Arthro-ophthalmopathy, Stickler's syndrome12q13.3
Ataxia telangiectasia11q22 - q23
Batten's disease (neuronal ceroid-lipofuscinosis)16q22
Blue-cone monochromasy (red/green)Xq28
Blue-cone pigment (Tritan color blindness)7q22-qter
Butterfly-shaped pattern dystrophy6p
Cataract, Coppock-like2q33 - q35
Cataract, posterior, polar16
Cataract, pulverulent, zonular, Coppock type1q21 - q25
Cataract, zonular, Mariner type16
Cataract, anterior, polar12p25 or 14q24
Cataract, anterior, polar2p26.2 or 4p15
Cataract, congenital, totalXp
Cerebrotendinous xanthomatosis2q33-qter2,3
CHARGE association6cen/8cen2,3
Coats' syndrome3p21 or 3q28
Cokayne's syndrome2q21
Collagen, type II, alpha-1 chain (Stickler's syndrome)12q13.1 - q13.3
Collagen 1, alpha-1 chain (Marfan's syndrome)17q21.3 - q22.05
Coloboma of iris2pter - p25.1
Color blindness, blue-cone monochromasyXq28
Color blindness, deutan (green-cone pigment)Xq28
Color blindness, protan (red-cone pigment)Xq28
Cone dystrophy 1Xp21.1 - p11.3
Cone dystrophy 2/defect of red-cone pigmentXq28
Cone dystrophy3q27
Cone-rod dystrophy18q21.1 - 22.2
Cone pigment, blue7
Congenital stationary night blindnessXp11.3
Craniosynostosis7p21.3 - 21.2
Dyslexia 115q11
Fabry's diseaseXq22
Familial exudative vitreoretinopathy11q13.5 - q22
Focal dermal hypoplasia (Goltz's syndrome)Xp22.31
Galactosemia 19p13
Glaucoma, juvenile open-angle1q21 - q31
GM1 gangliosidosis3p21-cen
GM2 gangliosidosis, AB variant5
Goldenhar syndrome (conjunctival dermoids)7p21.3 - 21.2
Green/blue eye color19
Gyrate atrophy10q26
Hurler-Scheie syndrome22q11
Incontinentia pigmentiXq27 - 28
Iris coloboma2pter - 2p25.1
Kearns - Sayre syndromemtDNA
Krabbe's disease (galactocerebrosidase)17
Leber's hereditary optic neuropathyXp1
Leber's hereditary optic neuropathymtDNA
Lowe's oculocerebrorenal syndromeXq25
Macular dystrophy, atypical vitelliform8q24
Macular dystrophy, vitelliform, Best's type11q13
Marfan's syndrome, type I alpha 217q21.3 - q22.05
Marfan's syndrome 115q15 - q21.3
Maroteaux-Lamy syndrome (mucopolysaccharidosis VI)5q11 - q13
Megalocornea, X-linkedXq12 - q26
Möbius's syndrome13q2
Morquio's syndrome B (mucopolysaccharidosis IVB)3p21 - cen
Multiple endocrine neoplasia II (IIA)10q21.1
Multiple endocrine neoplasia III (IIB)10q21.1
Myopia 1, X-linked, Bornholm eye diseaseXq28
Myotonic dystrophy19q13.1
Nance-Horan syndromeXp22.3 - p21.1
Neurofibromatosis 117q11.2
Neurofibromatosis 2 (acoustic neuroma)22q11 - q12.2
Nevoid basal cell carcinoma syndrome1p
Niemann-Pick disease (sphingomyelinase)17
Niemann-Pick, type Al sphingomyelinase)11p15.4 - p15.1
Norrie's diseaseXp11.4 - p11.3
North Carolina macular dystrophy6q16
Ocular albinism (Nettleship-Falls type)Xp22
Optic atrophy18
Optic atrophy (Kjer type)2p
Optic atrophy, polyneuropathy and deafnessXqdistal
Pelizaeus-MerzbacherXq21.3 - q22
Peripherin-retinal degeneration6p
Phenylketonuria12q22 - q24.1
Retinitis pigmentosa 18p11 - q21
Retinitis pigmentosa 2Xp11.4 - p11.23
Retinitis pigmentosa 3Xp21.1
Retinitis pigmentosa 4 (rhodopsin)3q21 - q23
Retinitis pigmentosa 6Xp21.3 - 21.2
Retinitis pigmentosa 7 (RDS, peripherin/RDS)6p21.1 - cen
Retinitis pigmentosa 819q13
Retinitis pigmentosa 97p15 - 13
Retinitis pigmentosa 107q
Retinitis pigmentosa (Rod cGMP phosphodiesterase)4p16.3
Retinitis pigmentosa (ROM1, digenic with peripherin/RDS)11p13
Retinitis pigmentosa (rd, RP-cGMP channel protein-1)4p14
Retinoblastoma13q14.1 - q14.2
RetinoschisisXp22.3 - p22.1
Rieger's syndrome4q22.2 - q25
Rod GMP phosphodiesterase4p16
Rod outer segment protein 111p13
S-antigen2q24 - q37
Sandhoff's disease5q13
Sanfilippo's syndrome12q14
Stargardt's 1 disease (autosomal-dominant)13q34
Stargardt's 2 disease (autosomal-dominant)6q
Stargardt's 3 disease (autosomal-recessive)1p
Stickler's syndrome12q13.1 - 13.3
Tapetochoroidal dystrophyXq21.1 - q21.2
Tay-Sachs disease15q22 - q25.1
Tritanopia7q22 - qter
Tuberous sclerosis 19q34
Tuberous sclerosis 211q22 - q23
Tuberous sclerosis 312q22 - q24.1
Usher's syndrome, 114q
Usher's syndrome, 21q
Vitelliform dystrophy8q
von Hippel-Lindau disease3p25 - p24
Waardenburg's syndrome2q35
Werner's syndrome8
Wieaclcer-WolffXq11 - q12
Wilson's disease13q14 - q21
Wolf-Hirshhorn syndrome4pter - p16.3
Zellweger's syndrome7q11.12 - q11.23



Albinism constitutes a group of inherited disorders characterized by defective melanin synthesis and decreased skin and ocular pigmentation (Fig. 2). Ocular manifestations include iris transillumination, foveal hypoplasia, photophobia, nystagmus, and a severe decrease in visual acuity. There are two types of albinism: ocular and oculocutaneous.93–95 Ocular albinism-can be either X-linked recessive or autosomal recessive; oculocutaneous albinism can be autosomal recessive or genetically heterogeneous. Recently, significant advances have been made in understanding the molecular biology of albinism, which has allowed genetic diagnoses on the basis of carrier detection and prenatal genetic testing.

Fig. 2. Ocular albinism. Decreased skin and hair pigmentation and iris transillumination defect can be seen.

X-linked ocular albinism is characterized by the presence of macromelanosomes and it is divided into two types: type 1 (Nettleshi-Falls type) and type 2 (Forsuus-Erikssontype).96 These patients demonstrate foveal hypoplasia, hypopigmentation of the retina and decreased visual acuity. The skin pigmentation, however, is normal. The OA1 gene has been mapped to chromosome Xp22.2- p22.3,97 whereas the OA2 gene is located in the Xp21.3-21.2 region.98

There are two types of oculocutaneous albinism: tyrosine-negative (type 1) and tyrosine-positive (type 2). Patients with tyrosine-negative (type 1) oculocutaneous albinism typically have no pigment in their hair at birth, and the amount of pigment in the skin and eyes is scarce. The OCA1 gene locus has been mapped to chromosome 11q14-21, where the tyrosinase gene is located. The human tyrosinase gene consists of five exons. The length of genomic DNA is more than 50 kb.99 Tyrosinase is initially translated into a 529-amino-acid polypeptide, which is subsequently cleaved to produce the mature tyrosinase protein.100,101 Various mutations have been detected in the tyrosinase gene in patients with oculocutaneous albinism type 1.102,103 The most common type of mutation is a single base substitution that gives rise to a different amino acid in the tyrosinase protein product.93 A striking feature of patients with these tyrosinase mutations is that most of them are compound heterozygotes with different mutant alleles, hence the wide range of tyrosinase expression and the corresponding severity of oculocutaneous albinism type 1 seen clinically.

Clinically, patients with tyrosine-positive oculocutaneous albinism -(OCA2) have pigmented hair at birth, and the amount of pigmentation in the skin and eyes increases with age. The OCA2 gene locus has been mapped to human chromosome 15q11.2-q12. The OCA2 gene has been shown to be a homologue of the mouse pink-eyed dilution gene. The OCA2 gene product appears to function as part of melanosomal membrane and is involved in the transport of tyrosinase.

Clinical diagnosis of oculocutaneous albinism using these findings is proving to be feasible. One of the major difficulties in the molecular genetic screening and prenatal diagnosis of oculocutaneous albinism type 1 is that there appears to be no hot-spot mutation in the tyrosinase gene, making it necessary to examine the entire gene sequence to search for mutations. This is analogous to the situation with retinoblastoma, in which no hot-spot mutation in RB1 has been identified. Screening for OCA1 patients using rapid screening techniques such as heteroduplex/SSCP has proved useful.95 In terms of treatment, there is evidence that loading the diet with excess tyrosine may be an effective therapy for patients with OCA2.104,105


Molecular genetic studies of aniridia have provided a fascinating opportunity to examine the molecular mechanisms of ocular embryogenesis. Since the early demonstration of the 11p13 locus for autosomal-dominant aniridia and the association between sporadic aniridia and Wilms' tumor, significant advances have been made in this field in recent years, leading to the identification of the human aniridia gene (PAX6).

Aniridia comprises a group of closely related panocular disorders with a common feature of iris hypoplasia (Fig. 3). Aniridia patients also can have a wide range of ocular findings, including cataract, foveal hypoplasia, nystagmus, corneal pannus, glaucoma, ectopia lentis, optic nerve hypoplasia, and strabismus. Aniridia can be genetically inherited either as an autosomal-dominant or an autosomal-recessive disorder (Gillespie's syndrome).106,107 It is well known that the sporadic form of aniridia is associated with Wilms' tumor, a pediatric nephroblastoma.108 The combination of sporadic aniridia and Wilms' tumor is commonly referred to as WAGR syndrome. This may appear to be somewhat peculiar, since the familial form of the disease (autosomal-dominant or autosomal-recessive) is not associated with Wilms' tumor.109 This apparent contrast is explained by the fact that PAX6 is located on chromosomal 11p13, in the vicinity of the gene for Wilms' tumor.45,46,110,110a In the autosomal-dominant form of aniridia, the DNA alterations involved are often minor (point mutations or small deletions) and affect only the aniridia locus, sparing the Wilms' tumor locus. In contrast, in the sporadic form of aniridia, there is often a large deletion of the gene segments involving the loci of both aniridia and Wilms' tumor, resulting in the clinical presentation of both diseases.

Fig. 3. Aniridia. Decreased skin pigmentation and small residual amount of iris can be seen.

PAX6 has been identified on chromosome 11p13.46,111–113 This gene contains 14 exons, is transcribed as a 2.7-kb mRNA, and encodes a 422-amino-acid protein. PAX6 may function as a transcriptional factor in regulating expressions of other genes in embryogenesis.112 Such an important role for PAX6 as the master control for gene expression in oculogenesis may explain the panocular manifestations in patients with aniridia. Aniridia and PAX6 have provided a valuable model system in the study of molecular mechanisms important in the embryogenesis of the eye.

Clinically, prenatal diagnosis can be carried out to detect PAX6 mutations in amniocytes.112 Such detection requires prior characterization of a PAX6 mutation in the family of the proband. In patients with the sporadic form of aniridia, it is important to detect deletions of chromosome 11p13 and the Wilms' tumor locus because these patients may have a 50% risk of Wilms' tumor development. Typically, karyotypes are examined and patients followed up with renal ultrasound. Molecular techniques are becoming available for direct detection of the number of copies of aniridia and Wilms' tumor genes in patients with aniridia, thereby offering a genetic test for the predisposition to Wilms' tumor.114–117


Axenfeld-Rieger syndrome consists of bilateral congenital abnormalities of the anterior segment of the eye associated with abnormalities of the teeth, midface, and umbilicus. Ocular findings include prominent, anteriorly displaced Schwalbe's line (posterior embryo toxon), peripheral iris strands extending to Schwalbe's line, and iris thinning with atrophic holes (Fig. 4). Axenfeld-Rieger syndrome is typically inherited as an autosomal-dominant disorder,118 but 25% of cases are sporadic. There is no sex predilection. Cytogenetic studies have mapped the Axenfeld-Rieger locus to chromosome 4q25.119–123 Based on these linkage studies, a candidate gene located in this chromosomal region that encodes for epidermal growth factor (EGF)124–128 has been chosen. The EGF gene is considered an excellent candidate gene because EGF binds to the tooth, and antibodies to EGF inhibit dental and eye development.125–127 Antisense oligonucleotides to EGF have been shown to block tooth formation in vitro.129 In addition, Raymond and co-workers126 and Jumblatt and associates130 have shown that the corneal endothelium has EGF receptors and undergoes morphologic changes when exposed to EGF.130 However the hypothesis that EGF is the Axenfeld-Rieger gene is yet to be proved because no causative mutations in EGF have been identified to date in patients with Axenfeld-Rieger syndrome. Alternative candidate genes in this chromosome 4q25 region are still being sought.124

Fig. 4. Rieger's syndrome. Iris abnormality is prominent.


Hereditary cataract can be transmitted as an autosomal-dominant131 or X-linked trait and can be associated with other ocular findings (e.g., microphthalmia, microcornea) and systemic manifestations (e.g., dental anomalies).96,131–134 The lens opacity is often central in X-linked congenital cataract (Fig. 5). Using RFLP, the locus for X-linked congenital cataract has been mapped to chromosome Xp21.1-22.3.135–137 Many other chromosomal loci have been described for various other types of cataract, including Coppock-like cataract (chromosome 2q33-35),138 Mariner-type cataract (chromosome 16q22),139,140 anterior polar cataract (chromosome 2p25, 14q24,141 and congenital total cataract (chromosome Xp).142,143

Fig. 5. Congenital cataract characterized by the central location of the lens opacity.


The recent discovery of the molecular defect in choroideremia is an excellent example of the power of molecular studies in advancing our understanding of disease pathogenesis. Choroideremia is a hereditary, bilateral, and progressive X-linked retinal degeneration characterized by central blindness in affected males during early adulthood. These patients have hemeralopia, decreased vision, and visual field constriction due to atrophy of the choroid and the retinal pigment epithelium (Fig. 6). One notable characteristic of choroideremia in contrast with other retinal degenerations, such as X-linked retinitis pigmentosa, is that carrier females of choroideremia have a typical fundus appearance consisting of linear retinal pigmentation with punctate area of pigment epithelial atrophy.

Fig. 6. Choroideremia. Atrophy of retinal pigment epithelium is evident.

The gene locus for choroideremia was mapped to the proximal region of Xq21.144–147 Through positional cloning, the achoroideremia gene has been identified and characterized in this region. Patients with choroideremia indeed have been found to have mutations in the putative disease gene.148–153 Up until 1993, however, very little was known concerning the biologic function of the choroideremia gene and its role in retinal degeneration. It was in the last three years, a significant breakthrough in this field was made by Seabra and colleagues,154,155 who reported that the choroideremia gene is in fact highly homologous to component A of rat Rab geranylgeranyl transferase, which belongs to a family of guanosine triphosphate-binding proteins. These proteins are believed to play important roles in the regulation of membrane transport and signal transduction. Furthermore, components of the rat Rab geranylgeranyl transferase have been found to be missing in patients with choroideremia.155 The molecular basis of choroideremia appears to be due to a defect in the membrane transport of proteins with attendant abnormalities in signal transduction. In addition, these studies suggest the exciting possibility that the genes for a host of well-characterized membrane transport proteins can be considered candidate genes for a variety of other hereditary retinal degenerations.


The molecular basis of human color perception has intrigued ophthalmologists for centuries. The remarkable advances achieved in this field in recent years are the result of modern molecular biologic studies, combined with insightful deductive reasoning and a close interaction between basic science research and clinical evaluation of patients.

Human color vision is mediated by three visual pigment proteins contained in cone photoreceptors: these pigments are sensitive to red (552 to 557 nm), green (530 nm), and blue (426 nm) light, respectively.156 Cone pigments function in bright light, in contrast to the rod photoreceptor pigment rhodopsin, which mediates vision in dim light. Visual pigment proteins are the main protein components of photoreceptor outer segments. Clinically, a person with normal color vision is called a trichromat. If one cone pigment is absent, the person is known as a dichromat. A protanopic dichromat is a person whose red cone pigment is missing, whereas a deuteranopic dichromat is a person whose green cone pigment is absent. Tritanopia, a rare disease, is the absence of the blue cone pigment. Patients lacking both the red and green pigments are known as having achromasy or blue-cone monochromasy. If all visual pigments are present but have altered absorption spectrums, the condition is termed anomalous trichromasia.

The phototransduction process starts with the capture of a photon by a visual pigment, leading to the change in conformation of 11-cis retinal chromophore contained in the visual pigment to a corresponding 11-trans structure. Activation of Gprotein and cyclic guanosine monophosphate (cGMP) phosphodiesterase causes an enzymatic cascade that eventually results in a change in the membrane potential of the photoreceptor and conduction of a visual signal.

To dissect the molecular basis of color vision, Nathans and co-workers157–160 reasoned in the early 1980s that if one assumes that the visual pigments have all evolved from a common ancestral gene, one can then clone the various human photopigments by starting with the bovine rhodopsin gene. Since the bovine rhodopsin protein sequence was known, Nathans and Hogness157 constructed a DNA probe with a nucleotide sequence corresponding to a small part of the bovine rhodopsin protein sequence. Using this DNA probe, they were able to obtain a complementary DNA (cDNA) clone and eventually sequence the entire bovine rhodopsin gene.

According to the plan of Nathans and Hogness,157 the bovine rhodopsin gene would serve as the anchoring molecule from which the human rhodopsin and all three human visual pigments were to be cloned. To isolate the human rhodopsin gene, they used bovine rhodopsin cDNA as a DNA probe and searched the human genome for homologous sequences. A human gene was identified and proved to be the human rhodopsin gene based on the fact that it shared a high degree of DNA sequence homology (89.7%) with bovine rhodopsin158–160 and that the amount of its mRNA in human retina corresponds well with previous observations.158 The human rhodopsin gene contains five exons and encodes for a protein with seven putative transmembrane hydrophobic domains. The gene is mapped to human chromosome 3q21.159

Nathans and co-workers next embarked on the cloning of all three human cone visual pigments. They reasoned that unlike the human rhodopsin gene, which shares a high degree of homology with bovine rhodopsin gene, the human cone pigments would share a lesser degree of DNA sequence homology. They therefore lowered the stringency requirement in the hybridization experiment. Again using the bovine rhodopsin cDNA as a probe, they obtained three human gene segments.160 The first segment showed 42% amino acid sequence homology with the bovine rhodopsin gene and was identified as the blue-cone pigment. The confirmation of the authenticity of the blue-cone pigment came from the observation that the amount of mRNA of the putative blue-cone pigment is about 1/150 of that of rhodopsin, consistent with the expectation based on the ratio of the number of blue cones to rods in the human retina160 and that the putative blue-cone pigment gene mapped to human chromosome 7, thus excluding it as being red or green cone pigment genes. The second and third human gene segments cloned were subsequently identified as the red and green cone pigments, respectively, based on the fact that (1) they also show 40% to 45% amino acid sequence homology with bovine rhodopsin and (2) the ratio of the amount of mRNA of the putative red and green pigments to that of rhodopsin agrees with the ratio of red and green cones to rods (1/30).160 In addition, these two putative red and green pigment genes were mapped to human X chromosome as expected, and studies in red-green color-blind men further confirmed the identities of these two genes.

Red and green pigment genes are arranged in a tandem array on the human X chromosome, with the red pigment gene in the upstream position (5' end). Each person has one red pigment gene, but a variable number (one, two, or three) of green pigment genes. The variation in the number and composition of these red and green pigment genes due to intragenic recombination events leads to variation in human color perception.159 In an analysis of blue-cone monochromasy patients who showed X-linked absence of both red and green pigment, Nathans and associates161 demonstrated inactivating DNA mutations in the red and green pigment genes. Furthermore, sequence changes in pigment opsins, which correspond to altered wavelengths at which the visual pigments absorb maximally,162–168 have been shown in patients. Other authors have found that defective color vision is caused by DNA mutations in the green pigment gene,169 and patients with tritanopia (autosomal-dominant disorder with lack of blue spectra sensitivity) have been shown to have mutations in the blue pigment gene.170 In addition, color vision defects as well as rhodopsin mutations have been found in patients with ADRP.47


Clinically congenital stationary night blindness (CSNB) becomes manifest as night blindness from birth, normal visual field, and paradoxic pupillary responses. Patients may have a normal or abnormal fundus. The correct diagnosis of the disease is important because it is generally not a progressive disease. CSNB can be inherited as an autosomal-dominant, autosomal-recessive, or X-linked disease.171–174 Myopia is often associated with the latter two modes of inheritance. A CSNB patient typically shows variable reduction in rod function, but a functionally intact cone system. The disease is divided into two types, complete and incomplete, which correspond to an absent or reduced rod function, respectively.

The gene locus for X-linked CSNB has been mapped to chromosome Xp11.3.175–178 This chromosome region appears to play an important role in retinal function because, in addition to the CSNB gene locus, it contains two loci for X-linked retinitis pigmentosa (RP2179–183 and RP3183–186) and the locus for ocular albinism type 2 (OA2).96 Clinically, myopia and CSNB appear to be coinherited.178 This phenomenon could be due either to a closely linked myopia gene or to a secondary pleiotropic effect of CSNB. Further investigation of genes in this region of X chromosome may significantly advance our knowledge of X-linked retinal diseases.


Ectopia lentis is clinically characterized by a lens displayed away from its optical axis (Fig. 7). Ectopia lentis can be part of a hereditary disorder, such as Marfan's syndrome, aniridia, homocystinuria, simple ectopia lentis, or congenital glaucoma.187 With regard to Marfan's syndrome, significant advances have been made recently in our understanding of the molecular pathogenesis of the disease. Marfan's syndrome is a common disorder of connective tissue that is characterized by skeletal, cardiovascular, and ocular abnormalities caused by abnormalities of fibrillin metabolism. The Marfan's disease-causing gene has been mapped to human chromosome 15.188–191 Because this chromosome region contains the fibrillin gene (FBN1),192 which is a major component of connective tissue, a candidate gene approach was taken to examine FBN1, and mutations have been identified in patients with Marfan's syndrome.192–196 Genetic tests are becoming available for the molecular diagnosis of Marfan's syndrome. This is significant because potentially life-threatening conditions are associated with this syndrome.

Fig. 7. Ectopia lentis. This patient has Marfan's syndrome with lens subluxed superiorly.


FEVR was first described by Criswick and Schepens197 as an autosomal-dominant disease of the retina and vitreous. It is well known that the disease can be inherited both as an autosomal-dominant trait198,199 or as an X-linked recessive trait.200 FEVR patients typically present with bilateral incomplete vascularization of the peripheral retina, retinal exudation, neovascularization, and fibrovascular proliferation, which may lead to tractional or exudative retinal detachment.197,201,202,202a The funduscopic appearance is similar to retinopathy of prematurity, except that the patients do not have a history of premature birth and oxygen therapy. FEVR has a penetrance of nearly 100%, but its expressivity is variable.202,202a

The chromosomal locus for the autosomaldominant type of FEVR has been mapped to chromosomal region 11q13.5-q22.203,204 It is intriguing to note that this locus is the same as that found for autosomal-dominant neovascular inflammatory vitreoretinopathy,205 clinically a distinct disease characterized by neovascularization of the retina and iris, inflammation, pigmentary retinopathy, and cystoid macular edema. It remains to be determined whether FEVR and autosomal-dominant neovascular inflammatory vitreoretinopathy share the same gene defect and underlying molecular pathogenesis.19

The X-linked recessive form of FEVR has been mapped to two possible chromosomal loci, Xq21.3 or Xp11.4-11.3.206 Clinically, the X-linked recessive form produces an earlier onset of disease than the autosomal-dominant form.206 It is noteworthy that the Xp11.4 region also contains the Norrie's disease gene, and patients with the X-linked form of FEVR have been found to have DNA mutations in the Norrie's disease gene.54 It is anticipated that further elucidation of the molecular basis of these diseases will significantly facilitate clinical diagnosis and management (see Norrie's Disease section later in chapter).


Glaucoma is an important and prevalent ophthalmic disease. A large number of inheritable ophthalmic diseases are associated with glaucoma, such as aniridia (autosomal-dominant), AxenfeldRieger syndrome (autosomal-dominant), neurofibromatosis (autosomal-dominant), and Lowe's syndrome (X-linked recessive) to name just a few.207 In this section, we will confine ourselves to primary open-angle glaucoma and discuss the recent advances in understanding the molecular basis of the disease.

Primary open-angle glaucoma (POAG) has a strong hereditary tendency. Anyone who has taken care of POAG patients understands the importance in soliciting a relevant family history of glaucoma. Numerous studies have shown that the prevalence of POAG in first-degree relatives of patients (2.8% to 13.5%) is significantly higher than that in the general population (about 1% in the white population).208–216 Attempts have been made to identify genetic markers associated with POAG.217 These markers include blood group antigens,215,218–222 HLA antigen association,218,221,222 ability to taste phenylthiourea,223 and association with diabetes mellitus224 and myopia.225 These studies, however, have not revealed any specific association of these genetic markers with POAG. At present, POAG is believed to have a polygenic or multifactorial inheritance.

As is often the case in the history of human genetics, a rare disease may provide a valuable opportunity to gain insight into a mechanism of a related common disease process. We have seen this in the example of retinoblastoma, where the study of this rare childhood tumor has proved a model system of tumor-suppressor genes and human carcinogenesis. This is due to the fact that in rare diseases, the clinical phenotype and the molecular pathogenic process can often be clearly delineated. With regard to POAG, one strategy is to identify a certain subset of less prevalent but clinically distinctive forms of the disease. Through dissecting the molecular pathogenic process involved in these distinctive entities, one may gain valuable insight into the mechanisms of more common disease processes. The study of juvenile open-angle glaucoma (JOAG) provided just this sort of valuable opportunity. It has been known for some time that JOAG is an autosomal-dominant trait.226–230 In 1993, Sheffield and associates231 reported genetic linkage of one form of familial open-angle glaucoma to chromosome 1q21-q31. Other groups have reported continued effort in cloning the causative gene in this chromosome region.25,232,233

The future identification of gene defects in JOAG and POAG will no doubt have a dramatic effect on the clinical management of glaucoma patients. Appropriate molecular diagnostic tests can be established. This is particularly important for glaucoma: because of its insidious manner of onset and the relatively asymptomatic nature of the disease in the early stages, patients often present for medical attention only when the disease is significantly advanced and irreversible damage to the optic nerve has occurred. Molecular diagnostic tests will enable the clinician to recognize individuals who are predisposed to or are at an early stage of the disease. Knowledge of the gene defects and their association with the severity of clinical presentation will have important prognostic value. Furthermore, recognition of key molecular events in the disease process will help create new forms of therapy for this condition.


Gyrate atrophy is an autosomal-recessive disease. Clinical findings of this disease include multiple sharply defined areas of chorioretinal atrophy separated from each other by thin margins of pigment (Fig. 8). The lesions typically begin in the midperiphery in childhood and then progress and coalesce to involve the entire fundus, sparing the fovea until later in the disease process, usually in midlife. Ornithine levels are markedly elevated in all body fluids.

Fig. 8. Gyrate atrophy. There are multiple sharply defined areas of chorioretinal atrophy separated from each other by thin margin of pigment.

Gyrate atrophy genetics is one of the few examples in ophthalmology of classical forward genetics: that is, the protein defect of the disease (ornithine aminotransferase [OAT]) was known before the chromosomal localization of the causative genes.234–236 An example of a nonophthalmic disease in which classical forward genetics was employed is sickle cell anemia237: the protein (hemoglobin) defect was known before the chromosomal localization of the gene. In the last few decades, however, reverse genetics has become the dominant strategy in modern gene cloning, as demonstrated in the case of CF.1

The gene encoding for OAT has been mapped to chromosome 10q26.238–241 The OAT gene consists of 11 exons and spans 21 kb of genomic DNA and 2.2 kb of mRNA.242 Several mutations in this gene have been identified in patients with gyrate atrophy.236,241–256b There are two types of gyrate atrophy: vitamin B6 (pyridoxine) responsive and vitamin B6 nonresponsive. The first group typically responds to the administration of vitamin B6, which reduces the serum ornithine level. It is still not known why OAT gene mutations preferentially affect ocular tissue, since OAT gene is expressed systemically.


The molecular genetics of Leber's hereditary optic neuropathy has become a prototypic example of mitochondrial inheritance. With the identification of the underlying molecular defect, this disease has provided a unique opportunity for examining the relationship between DNA mutations and clinical presentation of the disease.

Originally described in 1871 by Leber,257 Leber's hereditary optic neuropathy is characterized by rapidly progressive and painless visual loss in first one eye and then, within days to months, the other eye. The disease usually occurs in young men 15 to 30 years of age. Clinically there is mild swelling of the optic disc progressing for a period of weeks to optic atrophy. Small telangiectatic blood vessels can be seen near the optic disc (Fig. 9) that do not leak on intravenous fluorescein angiography. Visual acuity is often 20/200 to counting fingers, and visual field examination typically demonstrates a cecocentral visual field defect. It has been known since Leber's original description of the disease that Leber's hereditary optic neuropathy has a unique maternal transmission pattern: the genetic defect appears to be carried and transmitted from mothers to their children (usually sons), and affected fathers do not transmit the disease gene to their offspring. It was thus speculated that mutations in the mitochondria might be responsible for this disease because mitochondria are passed exclusively from mothers to offspring, not from fathers.

Fig. 9. Leber's hereditary optic neuropathy. Disc hyperemia and dilated and telangiectatic vessels can be seen.

In 1988, the first DNA mutation was identified in mitochondrial DNA in patients with Leber's hereditary optic neuropathy. Since then, a number of mitochondrial DNA mutations have been identified.258–265 These mutations can be categorized into two types: primary mutations, believed to be disease-causing DNA alterations; and secondary mutations, which act synergistically with primary mutations in modulating the clinical severity of the disease. Among the primary major mutations identified, point mutations in mitochondrial DNA nucleotide positions 11778, 3460, and 14484 account for 50%, 30%, and 10% of the disease, respectively, as seen clinically.258–265 The most prevalent mutation (at nucleotide position 11778) is a transition mutation that converts G to A, resulting in the replacement of a conserved amino acid arginine to a histidine. The 11778 mutation is associated with poor visual prognosis.266,267 Clinically, these mitochondrial mutations can be classified as high-risk (class I, or primary), intermediate-risk (class I/II, or mixed primary and secondary), or low-risk (class II, or secondary) mutations.

It is intriguing to examine the molecular pathogenesis of Leber's hereditary optic neuropathy, and several observations appear to be important in correlating DNA mutations with clinical disease:

  1. Mitochondria are vital intracellular organelles that supply energy for cellular metabolism through the electron transport chain system. Mitochondrial DNA mutations identified in Leber's hereditary optic neuropathy all appear to occur in genes involved in the mitochondrial metabolic process. For example, the 11778 mutation occurs in the gene ND4, which encodes subunit 4 of NADH dehydrogenase of the respiratory chain complex I, an enzyme necessary for the synthesis of adenosine triphosphate. Experimental evidence suggests that mutations such as ND4/11778 may affect the rate of NADH-dependent oxidative processes.268–269 It appears that mutations such as the 11778 mutation that occur at critical positions of the mitochondrial genome give rise to more severe phenotypes.
  2. There are a large number of genetic species of human mitochondrial DNA, and each person carries a mixed collection of these species (heteroplasmy), which may account for the wide range of clinical severity of Leber's hereditary optic neuropathy. The proportion of mitochondrial DNA mutations is likely to correlate with the penetrance and expressivity of the disease.
  3. The predilection of this disease for the optic nerve can also be explained by the high metabolic requirement of the central nervous system, as demonstrated experimentally by the high degree of mitochondrial respiratory activity within the anterior portion of the optic nerve.270
  4. The age-dependent onset of blindness may be explained by the following model. As one ages, there may be an accumulation of the number and severity of mitochondrial DNA mutations, resulting in an age-related increase in the inhibition of the mitochondrial electron transport system.260 Because of these and other factors, such as accumulation of environmental insult, the mitochondrial electron transport capability may at some point fall below the critical threshold needed by highly metabolically active tissues such as the optic nerve, and thus the disease becomes manifest.

Clinically, advances in the molecular pathogenesis of Leber's hereditary optic neuropathy have had a major impact in the management of this disease. For patients with a family history of the disease, mitochondrial DNA mutations can be identified, and the visual prognosis depends on the type of mutations present. For sporadic cases, the diagnosis of this disease can also be established through the identification of mitochondrial DNA mutations. Many questions still remain, however. The molecular studies fail to account for several features of Leber's hereditary optic neuropathy, such as male dominance of the disease, reduced penetrance, later age of onset for women, and the apparently healthy state of many carriers of the mitochondrial DNA mutations. Linkage studies have been reported that show X-chromosome involvement, which may explain the male dominance of this disease271,272; however, these studies have not been confirmed.273–275 The recurrence risk of the disease in genetically defined Leber's hereditary optic neuropathy is still difficult to assess accurately.258 Despite the success in identification of the molecular defect of the disease, very little progress has been made with regard to treatment. The use of steroids, hydroxocobalamin, or cyanide antagonists has not proved effective.276–280 Molecular studies of this fascinating genetic disease have, however, significantly advanced the field of mitochondrial genetics and will continue to provide a rare opportunity to delineate the molecular pathogenesis of this disease.281


Macular degeneration comprises a heterogeneous group of disorders characterized by progressive degeneration of macular and retinal pigment epithelium and loss of central vision (Fig. 10). Age-related macular degeneration (ARMD) is the leading cause of legal blindness in patients older than 65.282–284 There is a strong genetic predisposition to macular degeneration, 20% of persons with ARMD having a significant family history.285 There is a significantly increased risk of ARMD developing in a person if his or her twin or first-degree relative is affected.286–288 Despite the evidence of genetic susceptibility to ARMD, identification of the underlying genetic causes has remained a challenging task to ophthalmic researchers. In the past few years, however, significant progress has been made in this field, particularly with regard to several inherited forms of macular degeneration.

Fig. 10. Age-related macular degeneration. This patient has multiple scattered drusen and two well-defined areas of retinal pigment epithelium detachment, one through fovea and one inferior to the fovea.

One form of macular degeneration that has been extensively studied with the use of molecular techniques is North Carolina macular dystrophy.289 The disease has been so named based on an apparent founder effect in the Carolinas more than 200 years ago.289,290 Clinically, North Carolina macular dystrophy is an autosomal-dominant disease with congenital or infantile onset. These patients exhibit macular drusen and decreased central vision. The gene responsible for this disease has been mapped to human chromosome 6q16.21,291–294a

Best's vitelliform macular dystrophy is an autosomal-dominant disease. First to describe this disorder, Best295 found that these patients typically exhibited yellow, round subretinal lesions similar to an egg yolk or in some cases to a pseudohypopyon (Fig. 11). The lesions are located in the fovea and are often bilateral, measuring approximately one to two disc areas in size. Approximately 10% of eyes have multifocal lesions in the extrafoveal region. Patients with this disease often have a normal electroretinogram but an abnormal electro-oculogram. Carriers of this disease may have an abnormal electro-oculogram despite having normal fundi. The foveal lesion may degenerate, potentially resulting in macular choroidal neovascularization, hemorrhage, and scarring. In the scar state, it may be indistinguishable from ARMD.

Fig. 11. Best's disease. A yellow, round subretinal lesion (“egg yolk”) can be seen in the macula.

The chromosomal location for Best's disease has been mapped to human chromosome 11q13.296–298 A candidate gene located in this region, ROM1, has been examined,299–303 but no mutation in ROM1 has been detected to date in patients with Best's disease.

Stargardt's juvenile macular dystrophy (fundus flavimaculatus) is one of the most common inherited macular degenerations in childhood. First to describe this disorder,304 Stargardt found that patients with this disease usually present with bilateral decreased vision in childhood or young adulthood. In the early stages, the decrease in vision is often out of proportion to the clinical ophthalmoscopic appearance, and one must be careful not to label an affected child as a malingerer. Clinically, patients with Stargardt's disease can have yellow or yellow-white fleck-like deposits at the level of the retinal pigment epithelium, usually in a pisiform (fish-tail) configuration (Fig. 12). Atrophic macular degeneration can also occur, appearing as one or more of the following: macular retinal pigment epithelial changes, a “beaten metal” appearance, and marked geographic atrophy. The fluorescein angiographic finding of a “silent or dark choroid” is present in 85% of cases; a “bull's eye” window defect occurs in advanced cases.

Fig. 12. Stargardt's disease. Diffuse yellow, fleck-like deposits can be seen at the level of the retinal pigment epithelium.

Stargardt's macular dystrophy is typically transmitted as an autosomal-recessive disease. A locus for the recessive form of the disease has been mapped to the short arm of chromosome 1.305 Recently, two chromosomal loci have been identified for the dominantly transmitted form of the disease, one on the long arm of chromosome 13 and the other on the long arm of chromosome 6.306,307

Butterfly-shaped pigment dystrophy is a relatively rare macular dystrophy characterized by bilateral, symmetric pigmentary changes resembling the shape of a butterfly.308–311 Patients typically present with progressive atrophic changes in the fovea and a gradual decrease in vision. Mutations have been found in the human peripherin/RDS gene of patients with this disease.312–314 RDS stands for “retinal degeneration slow,” a homologue of the mouse gene.315 Peripherin is a membrane-associated glycoprotein found in the outer segments of photoreceptors and is thought to provide structural stability to photoreceptor discs. The peripherin/RDS gene has been mapped to human chromosome 6p. Mutations in this gene have also been identified in patients with ADRP.289,316


Neurofibromatosis is a neuro-oculocutaneous syndrome that consists of types 1 and 2. Neurofibromatosis type 1 is also known as peripheral neurofibromatosis or von Recklinghausen's disease. Clinical presentations include neurofibromas, café-au-lait spots, and Lisch nodules of the iris (Fig. 13). Other ocular findings in this type include iris, choroidal, and retinal hamartomas; optic nerve gliomas and meningiomas; and retinal astrocytic hamartomas.

Fig. 13. Neurofibromatosis. Lisch's nodules of this iris can be seen.

As in the case of retinoblastoma, recent advances in the molecular genetics of neurofibromatosis have significantly contributed to the field of human cancer genetics, particularly in the field of tumor-suppressor genes. Like RB1, the gene responsible for neurofibromatosis is believed to be a tumor suppressor as well. The NF1 gene is located on human chromosome 17q11.2. It is one of the largest human genes known, spanning a genomic DNA region of 350 kb. Because of its large size, NF1 is believed to have a high spontaneous mutation rate (1 × 10-4). This is clinically important because spontaneous DNA mutations give rise to sporadic diseases (new germline mutations or somatic mutations) and therefore a lack of family history does not necessarily rule out the diagnosis of this genetic disease. In fact, approximately 50% of neurofibromatosis type 1 patients are new mutants.27 NF1 consists of 51 exons and encodes for an mRNA of 11 to 13 kb.317–319 The coding region of NF1 specifies a protein of 2881 amino acids and a molecular weight of 327 kilodaltons (kd). The neurofibromatosis type 1 protein is believed to be a tumor suppressor.320,321 A normal person has two intact copies of NF1, whereas a patient with neurofibromatosis type 1 has one defective copy of the gene. If mutations occur in this remaining NF1, the neurofibromatosis type 1 protein will be inactivated and its tumor-suppressive activity lost, leading to tumorigenesis. Clinically, standard DNA tests are not yet available because of the large gene size of NF1 and the wide variety of mutations present. The diagnosis of neurofibromatosis type 1 currently is still based on clinical criteria.

In contrast to neurofibromatosis type 1, neurofibromatosis type 2 is associated with the development of central nervous system tumors such as schwannomas, meningiomas, and ependymomas. Genetically, these two disease types are distinctively different. The NF2 gene has been mapped to human chromosome 22. A candidate gene in this chromosomal region that encodes a membraneorganization protein has been identified based on the experimental evidence that constitutional intragenic mutations are present in patients with neurofibromatosis type 2.322,323 The neurofibromatosis type 2 protein is believed to be a membrane-organization protein; it may also be a tumor suppressor, as is the case for the neurofibromatosis type 1 and retinoblastoma proteins. Tumors containing NF2 mutations have been shown to have lost the normal allele.324,325 Clinically, mutation detection is becoming possible to aid in the diagnosis of neurofibromatosis type 2.


Norrie's disease is an X-linked disorder characterized by progressive atrophy of the retina, deafness, and mental disturbances.326–328 First to describe this disease in 1927,324 Norrie found that it typically affects males, who present with bilateral retinal detachment at birth or in early infancy. The retinal detachment is believed to be caused by a primary retinal dysplasia. Associated ocular diseases include glaucoma, iris atrophy, and cataract with systemic involvement, including deafness and mental retardation.

Although deletions in the monoamine oxidase (MAO) gene have been reported in patients with Norrie's disease,325MAO is more likely just a marker for the localization of Norrie's disease gene, rather than being directly involved in the pathogenesis of the disease.325,329 Using yeast artificial chromosomes, a candidate gene for Norrie's disease was cloned in330,331 with the use of positional cloning techniques. Norrie's gene contains three exons. Only exons 2 and 3 are translated, however, into a 133-amino-acid protein.330 Norrie's protein shares sequence homology both with proteins involved in cellular adhesion332 and with growth factors such as transforming growth factor and nerve growth factor.333 This raises the intriguing possibility of the role of Norrie's protein in signal recognition and neuronal connections. These mechanisms could then explain why alterations in Norrie's protein could lead to retinal dysplasia.

From a clinical standpoint, detection of mutations in Norrie's gene is feasible, since 75% of point mutations observed in Norrie's gene occur in exon 3.334,335 Prenatal diagnosis and carrier detection have been reported.335 As discussed previously, DNA mutations in Norrie's gene have also been found in some patients with FEVR.54 These findings will have significant impact on clinical diagnosis of these conditions. The cloning and identification of Norrie's disease gene have advanced our understanding of the disease pathogenesis as well as the molecular mechanisms involved in ocular development.


Retinitis pigmentosa is one of the most common forms of hereditary blindness. Clinically it is characterized by difficulty with night vision and loss of peripheral vision. Decrease in central visual acuity and color perception may ensue. Decreased amplitudes are typically demonstrated on electroretinograms. Funduscopically, retinitis pigmentosa may show clumps of pigment dispersed throughout the peripheral retina in a perivascular pattern with a “bone spicule” appearance (Fig. 14). Optic disc pallor is often present, and arterioles are often constricted.

Fig. 14. Retinitis pigmentosa. “Bone spicule” changes of the retinal pigment epithelium can be seen.

Retinitis pigmentosa is grouped into two types: type 1 (D-type), which is characterized by a young age of disease onset; and type 2 (R-type), which has a variable age of onset. Retinitis pigmentosa can be inherited as an autosomal-dominant, autosomal-recessive, X-linked dominant, or X-linked recessive trait. The most severely affected phenotypes are seen in the X-linked recessive form of the disease. Genetic linkage studies on a large Irish pedigree mapped the locus for one form of ADRP to human chromosome region 3q.62 Since this region contains the rhodopsin gene,157,158 a candidate gene approach was undertaken and a point mutation was found in the rhodopsin gene (pro23his).47

Since then, more than 70 additional mutations in the rhodopsin gene have been identified in patients with ADRP (Table 2).14,20,24,47,62–92,335a As can be seen from Table 2, most of these mutations are transition mutations (i.e., one purine is substituted for another, such as A for G or vice versa), which greatly outnumber transversions (i.e., purine to pyrimidine or vice versa). This is intriguing since if nucleotide substitutions were random, there should be twice as many transversions as transition mutations.24 This is because every base pair can undergo two transversions but only one transition mutation. The excess of transition mutations are believed to be related to the methylation of cytosine residues and subsequent deamination that form thymidine, a mutational process often observed in other human genes. The location and diversity of the rhodopsin mutations found in retinitis pigmentosa patients may affect the threedimensional structure of the rhodopsin protein, resulting in its functional alteration. For example, the cysteines at codons 110 and 187 form a disulfide bond, and lysine at codon 296 serves as the attachment site of 11-cis-retinal. Alterations in these amino acids can significantly affect the structure and function of rhodopsin. It can also be seen from Table 2 that the amino acid proline is disproportionally affected in these rhodopsin mutations, consistent with the structural stabilizing role of proline in the three-dimensional folding of the protein.


TABLE TWO. List of Mutations Identified in the Rhodopsin Gene in Autosomal-Dominant Retinitis Pigmentosa

CodonSequence ChangeAmino Acid Change
68 – 71del:CTGCGCACGCCTdel:Leu-Arg-Thr-Pro
 GT-TTIntron 4 donor splice site mutation
 150 bp ins + 30 bp del starting at 5145Intron 4-exon 5 insertion/deletion
340 – 34842 bp del8 a.a. del
340 – 348ACG-A G (5250)del 340 – 348, ins 19a.a.
341 – 3488 bp del (5252 – 5259)del 341 – 348, ins 9a.a.
341 – 3438 bp del2 a.a. del & fr. sh.

a.a. = amino acid; bb = base pair; del = deletion; fr. sh. = frame shift; ins = insertion.
(Adapted from Wang MX, Sandos R, Crandal A, Donoso LA: Recent advances in the molecular genetics of retinitis pigmentosa. Curr Opin Ophthalmol 6(III):1, 1995)


Rhodopsin gene mutations account for approximately 10% of all cases of retinitis pigmentosa, and 25% of all cases of autosomal-dominant cases. In addition to the rhodopsin gene, at least nine other distinct genetic loci have been implicated in retinitis pigmentosa (Table 3). Most of these loci have been identified through linkage studies. Five specific genes have been identified: rhodopsin, peripherin/RDS, the beta-subunit of rod cGMPphosphodiesterase, RP-cGMP channel protein-1, and the ROM1 genes. The explanation for the involvement of multiple proteins in this disease process may lie in the fact that since there are many proteins involved in the visual transduction pathway (Fig. 15), mutations and therefore loss of function of any of the critical proteins may lead to the same end result: photoreceptor degeneration. In addition to monogenic inheritance, there is recent evidence of a digenic inheritance of retinitis pigmentosa87 in which only those persons who are doubly heterozygous for both peripherin/RDS and ROM1 loci are affected. Biochemically this is particularly intriguing, since these two proteins appear to interact through noncovalent binding, which is responsible for the structural stability of the photoreceptor outer segment disc.


TABLE THREE. List of Genetic Loci Associated with Retinitis Pigmentosa

CategoryDisorderModeLocationMutationSequence ChangeGene/Protein
Retinitis pigmentosaRP-1AD8p11 - q21  ND
 RP-2XL-RXp11.23  ND
 RP-3XL-RXp21.1  ND
 RP-4*AD/AR3q21 - q24Intron #4 donor splice site mutationGT-TT GAG-TAGRhodopain
 RP-6XL-RXp21.3 - p21.2  ND
 RP-7AD6p21.1 - cen  Peripherin/Retinal
 (Human homologue of mouse rds)  Cys 118/119 delTGC-delDegeneration Slow (RDS)
    Lys 153/154delAAG-del 
 RP-8AD19q13.4  ND
 RP-9AD7p15.1 - p13  ND
 RP-10AD7q  ND
 RP-human homolog of mouse rdAR4p16.3  Rod cGMP phosphodiesterase, B-subunit (B-PDE)
 RP-cGMP channel protein-1AR4p14 - q13  Rod cGMP channel protein
    Pro496(1-bp del)CCC-CC 
RP and congenital hearing lossUsher's syndrome type IAAR14q32  ND
 Usher's syndrome type IBAR11q13.5  ND
 Usher's syndrome type ICAR11p14 - 15.1  ND
 Usher's syndrome type IIAAR1q42-ter  ND

AD = autosomal dominant; AR = autosomal recessive; bp = base pair; del = deletion; ND = not determined; XL-R = X-linked recessive.


Fig. 15. Phototransduction pathway. Numerous proteins involved in this pathway are implicated in retinal degenerations. (Modified from Berson EL: Retinitis pigmentosa. Invest Ophthalmol Vis Sci 34:1659, 1993)

Once mutations are identified, elucidation of their functional significance and their role in retinal degeneration is a more formidable task. There is biochemical evidence that some mutant rhodopsin proteins fail to fold properly, resulting in an accumulation of the protein in the endoplasmic reticulum, leading to photoreceptor degeneration.63 Overexpression of the normal rhodopsin protein is also believed to contribute to the retinal degenerative process.336 There is increased evidence that photoreceptor cell death occurring in diseases such as retinitis pigmentosa is not the direct result of primary mutational events as described above. Rather, these various mutational events may converge and funnel into a common pathway of cell death, such as apoptosis. Apoptosis, or programmed cell death, is a process by which damaged cells are removed. The purpose of apoptosis is for self-protection of the organism.

There is evidence that photoreceptor degeneration seen in retinitis pigmentosa may indeed involve programmed cell death. For example, cone photoreceptor death has been observed in addition to rod degeneration in retinitis pigmentosa, where the primary mutational event is rhodopsin gene mutation.88 There is evidence that photoreceptors containing the wild type and mutant rhodopsin genes degenerate simultaneously.337 The rapid progress in the elucidation of the fundamental molecular events involved in retinitis pigmentosa will no doubt have a significant impact on the clinical management of these patients. For example, recognition of a common cellular degenerative pathway such as apoptosis may suggest powerful new methods of therapeutic intervention.


The study of the molecular biology of retinoblastoma has led to the recent development of an entirely new concept in human cancer genetics: the tumor-suppressor gene. Retinoblastoma has become the prototypic example of tumors caused by mutations in tumor-suppressor genes and has significantly increased our understanding of the molecular mechanisms of tumorigenesis.

Retinoblastoma is the most frequent malignant neoplasm of the eye in childhood, occurring in approximately 1 of 20,000 live births (Fig. 16). It has both familial and sporadic forms: 6% of the patients have a family history of the disease; the remaining 94% have the sporadic cases.338 Approximately 30% of the sporadic cases are caused by new germline mutations, whereas the remaining 70% are due to somatic mutations. Bilateral retinoblastoma is considered to be hereditary (arising from either an inherited mutation or a new germline mutation). However, a unilateral retinoblastoma still has a 20% chance of being hereditary (i.e., new or old germline mutations).

Fig. 16. Retinoblastoma. A white, calcified tumor can be seen near the optic disc.

In 1971, Knudson339 reported a landmark study of retinoblastoma in which he suggested that the disease may arise from two mutational events. In the hereditary form of retinoblastoma, a patient inherits one mutant allele and a second mutation occurs somatically. In contrast, the sporadic form of the disease requires two successive somatic mutations in one cell to give rise to tumor. Demonstration of the specific loss of heterozygous chromosome 13q14 markers in retinoblastoma not only implicated this chromosome in the pathogenesis of the disease, but also provided evidence supporting Knudson's “two-hit” theory.

The RB1 gene was cloned and sequenced in 1986 and340–342 It not only provided direct proof of Knudson's two-hit hypothesis at the molecular level, but also helped open a new field in human cancer genetics, namely the study of tumor-suppressor genes. Two examples of cancer-causing genes are oncogenes and tumorsuppressor genes. Oncogenes, when activated, facilitate malignant transformation, whereas tumor-suppressor genes inhibit tumor development. A critical step in the identification of RB1 was the isolation of a DNA fragment from a human chromosome 13 library, which was used to construct a DNA probe that recognized a transcript from normal human retinal cells but was absent in retinoblastomas, a finding consistent with the property expected of the wild-type retinoblastoma gene.

RB1 is a large gene, spanning approximately 200 kb of genomic DNA. It contains 27 exons and encodes for a 110-kd nuclear protein.343 Approximately 20% of retinoblastomas contain gross chromosomal deletions, whereas the remaining 80% of tumors contain small DNA mutations, including point mutations. In Figure 17, we schematically summarize the mutations found to date in RB1.11,18,20,28,29,37,49,344–356 Notably, a significant proportion of the mutations occur in the noncoding regions of the gene, which may affect RNA splicing, giving rise to a grossly altered retinoblastoma protein. Epigenic changes, such as hypermethylation of the promoter region of RB1, also have been implicated in the pathogenesis of this disease.

Fig. 17. Spectrum of mutations in the retinoblastoma gene. (Adapted from Wang MX, Donoso LA: Gene research and the eye. Curr Opin Ophthalmol 4(III):102, 1993)

The retinoblastoma protein is a DNA-binding phosphoprotein located in the cell nucleus. It consists of 928 amino acids with a molecular weight of 110 kd.357,358 The effort to elucidate the function of the retinoblastoma protein has been carried out through several approaches,359,360 as follows:

  1. The retinoblastoma protein is inactivated once it is phosphorylated. The retinoblastoma protein appears to exert its tumor-suppressive activity by regulating cell division and proliferation.361 The retinoblastoma protein inhibits cell division by binding to cellular transcription factors such as E2F. Once the retinoblastoma protein is inactivated through phosphorylation, however, E2F is released and free to exert its cellular proliferative activity,362,363 leading to unchecked cell divisional cycles beyond the G1/S boundary.
  2. In addition to E2F, the retinoblastoma protein has been shown to interact with a number of vital proteins involved in cellular transformation, such as adenovirus E1A,364 SV40 large T antigen,365 human papillomavirus E7,366 and Epstein-Barr virus EBNA-5.367,368 The binding of these viral oncoproteins to the retinoblastoma protein inactivates its tumor-suppressive activity, leading to vital transformation and tumorigenesis.
  3. There appears to be a family of retinoblastoma protein-like factors, such as p107, p130, and p300, which may play a role in the regulation of cell cycles similar to that of the retinoblastoma protein.369–371
  4. Transgenic mice have been created to study the effect of mutant retinoblastoma genes. It appears that mice that are homozygous for the mutant retinoblastoma gene die in utero with a number of developmental defects involving the nervous and hematopoietic systems,372,373 suggesting that RB1 may be critical for development. Interestingly, mice heterozygous for the mutant retinoblastoma allele are not found to have retinoblastoma, but rather pituitary tumors.372,373
  5. Loss of the retinoblastoma protein appears to be a prognostic factor in many other forms of human cancers, such as bladder, breast, and testicular cancers and sarcomas,374–388a implicating a more global role of RB1 in human biology.


First described by Stickler in 1965,389 Stickler's syndrome (arthro-ophthalmopathy) is an autosomal-dominant disorder that affects the eyes, ears, joints, and skeleton. Ocular involvement includes severe and progressive myopia, optically empty vitreous, perivascular lattice, cataract, glaucoma, and retinal detachment (Fig. 18). Systemically, patients may present with mandibular hypoplasia, cleft palate, hypermobility or hypomobility of the joints, epiphyseal dysplasia, and progressive sensorineural hearing loss. Linkage studies demonstrated linkage of Stickler's syndrome to the gene for type II procollagen (COL2A1), which is located on chromosome 12q.390–394 DNA sequence analysis revealed a mutation that converts the codon CGA for the amino acid arginine at position a 1-732 to TGA, which is a stop codon.390 This appearance of a premature stop codon truncates the type II procollagen protein and is believed to be pathogenic. A second mutation in the COL2A1 gene that also creates a premature stop codon was subsequently described.395 It is not known, however, why such constitutional mutations produce severe pathology in the eye, which contains a relatively small amount of type II collagen. In contrast, these mutations appear to produce only a mild effect on the cartilaginous structures of the rest of the body.390

Fig. 18. Stickler's syndrome. Perivascular changes can be seen in the retinal pigment epithelium.


The classic ocular finding in tuberous sclerosis (Bourneville's disease) is astrocytic hamartomas of the retina. These are benign lesions manifesting as a characteristic mulberry-like appearance. Calcification may occur in the retinal lesions, which are located in the nerve fiber layer. Multiple hamartomas can be present in the skin, cerebral cortex, and kidney (Fig. 19). Tuberous sclerosis is inherited as an autosomal-dominant trait. Genetic linkage studies include reports of linkage to chromosome 9q32–9q34,396 chromosome 16p13,397 and chromosomes 11q22-23398 and 11q14-23.399 No candidate genes have been identified. It appears that tuberous sclerosis may have a significant nonallelic heterogeneity involving multiple genetic loci.25,54,202a

Fig. 19. Tuberous sclerosis. Multiple facial harmatomas.


Malignant melanoma of the uveal tract is the most common primary intraocular malignant tumor in the adult population, with an incidence of about 6 cases per million per year.338 Approximately 50 families have been reported in the literature with an inherited form of uveal melanoma.400–405a An autosomal-dominant mode of inheritance with incomplete penetrance has been proposed.406 Recently in a series of 4500 patients, 17 families were described where a first-degree relative of the proband was affected with primary uveal melanoma, strongly supporting a hereditary basis for this disease.407 A gene encoding for a uveal melanoma-associated antigen has been cloned, showing extensive sequence homology with several proteins involved in growth regulation (Fig. 20).408 The detection of this or other melanoma-associated antigens in systemic circulation may offer the potential for improved management of patients with uveal melanoma.20,408a

Fig. 20. Uveal melanoma. A uveal melanoma (top) showing the anterior location of the tumor. The same tumor (bottom) stained with monoclonal antibody MAb8-1H. (Adapted from Wang MX, Donoso LA: Gene research and the eye. Curr Opin Ophthalmol 4(III):102, 1993)


von Hippel-Lindau disease is an autosomaldominant disease jointly named for von Hippel, a German ophthalmologist who described patients with retinocapillary hemangioma,409 and Arvid Lindau, a Swedish neurologist who observed cerebellar and retinocapillary hemangioma (Fig. 21), renal cell carcinoma, and pheochromocytoma in these patients.410

Fig. 21. von Hippel-Lindau disease. Retinal capillary hemangioma with a large feeding vessel.

In recent years, significant progress has been made with regard to the molecular biology of this disease. A gene predisposing persons to von Hippel-Lindau disease was mapped to chromosome 3p25-p26 and was subsequently cloned.411 The von Hippel-Lindau disease gene appears to be another tumor-suppressor gene, and loss of the function of the protein leads to tumorigenesis. Alteration of the von Hippel-Lindau gene, including rearrangements and deletions, were found in 28 of 221 von Hippel-Lindau kindreds. The von Hippel-Lindau gene is evolutionarily conserved and encodes two transcripts with molecular weights of approximately 6 and 6.5 kb. The partial sequence of the inferred gene product shows no homology to other proteins, except for an acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei. Based on clinical findings of vascular abnormalities, it has been speculated that the von Hippel-Lindau protein may be part of the structural component for blood vessel walls.412


X-linked retinoschisis is a bilateral ocular disease occurring in males. Clinical findings include separation of the nerve fiber layer from the outer retinal layers in the retinal periphery, with the development of nerve fiber-layer breaks occurring most frequently in the inferotemporal quadrant of the fundus. Posterior pole findings include cystoid foveal changes, with retinal folds that radiate from the center of the foveal configuration (petaloid pattern). Unlike the cysts of cystoid macular edema, however, cystoid changes in the X-linked retinoschisis do not stain on fluorescein angiography.413,413a-d

The chromosomal locus for the X-linked retinoschisis has been mapped to Xp22.2-p22.1.53,413e Allelic heterogeneity may account for the wide spectrum of clinical presentation of this disease. Differential diagnoses include retinopathy of prematurity, Goldmann-Fabre disease, retinitis pigmentosa, FEVR, Norrie's disease, and Stickler's syndrome. Further molecular characterization of these diseases may aid in their clinical differentiation.

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A genetic study begins with patients. Collecting appropriate clinical data is the first important step. In this respect, the role played by ophthalmologists is essential. Appropriate clinical issues regarding genetic diseases need to be addressed with patients; pedigrees must be drawn and DNA samples (often from peripheral blood) collected. A practicing ophthalmologist should be familiar with the major principles of modern molecular genetics, work closely with ophthalmic researchers, and provide genetic counseling to patients with the help of geneticists. With the rapid development of molecular genetics in recent years and the increasingly mature technologies for genetic analysis in clinical settings, ophthalmologists will play an increasingly important role in molecular genetics.413f


Many techniques are available for detecting gross deletions or DNA alterations, including the Southern blot analysis, allele-specific hybridization, competitive oligonucleotide priming, the amplification refractory mutation system, and the oligonucleotide ligation assay.7,9,20,414–416 Recently, there has been a proliferation of rapid techniques for identifying the presence of small DNA alterations such as single-base-pair mutations, including the SSCP, the RNase protection assay, denaturing gradient gel electrophoresis, constant denaturing gel electrophoresis, primer-specified restriction map modification, and detection of mutations with hydroxylamine and osmium tetroxide.7,9,20,41,417–421 This progress has greatly aided in the clinical application of DNA mutation detection as a means for genetic diagnosis.

Using combinations of the above-described laboratory techniques, one may employ the following approaches to genetic testing360:

  1. Direct molecular detection of mutations: This work may be time-consuming and expensive, but if successful it could reveal oncogenic DNA mutations that are invaluable, as demonstrated in retinoblastoma.28,49
  2. Detection of gross rearrangements: One can accomplish this using karyotyping and the Southern blot analysis.
  3. Linkage analysis: Using a set of appropriately chosen DNA markers, one can characterize mutant alleles in patients and offspring who carry the identified mutant allele. Linkage analysis does not, however, reveal the actual DNA alteration responsible for the disease analyzed.

For X-linked recessive disease, typically only males are affected. Female carriers, however, can manifest the disease clinically to a variable extent through processes such as unbalanced X chromosome inactivation and reciprocal X:autosome translocation. X chromosome inactivation is a process by which one copy of the X chromosome is inactivated to maintain a balanced gene dosage. Nonrandom X-chromosome inactivation can lead to a greater retention of the mutant X chromosome (carrying disease mutations) than the corresponding wild type, leading to a disease phenotype. For example, in Norrie's disease, X-chromosome inactivation is believed to be responsible for the clinical disease in female patients.422 Clinical manifestation of an X-linked recessive disease in female carriers can also be due to X-autosome translocation. Presumably such a process can lead to chromosomal imbalance and retention of the copy of the X chromosome containing mutations. In Norrie's disease, reciprocal translocation t(X:10)(p11:p14) has been reported, resulting in the clinical presentation of the disease in a female carrier.202


Genetic counseling is an important aspect of ophthalmic practice because many ocular diseases can be inherited. In particular, genetic diagnosis is of significant value in certain ocular diseases in which DNA mutations are present, thus predisposing patients to these diseases. Because DNA diagnosis can often be made before the onset of clinical symptoms and signs of these diseases, ophthalmologists should use this important information in assessing clinical prognosis and treatment. For example, different mutations in the rhodopsin gene are associated with varying degrees of severity in the clinical presentation of retinitis pigmentosa. This is of value to patients with regard to visual prognosis. Another example is retinoblastoma caused by transmissible germline mutations. If a child is born with retinoblastoma, the family may be concerned with the well-being of future children and recurrence risks need to be assessed. Patients with a family history of retinoblastoma may want to know if they harbor a gene mutation and whether an unborn child carries the dominant mutant allele. In general, genetic counseling should consist of the following six logical steps.11,423

  1. Medical diagnosis: The clinician establishes an appropriate medical diagnosis and examines the proband as well as other relevant family members. Laboratory studies such as karyotyping, biochemical and molecular analysis of blood, and tumor samples are carried out.
  2. Pedigree analysis: Physicians should attempt to obtain a complete three- to four-generation family pedigree. Special attention should be paid to incidence of miscarriage, stillbirths, or mildly affected individuals.
  3. Assessment of recurrent risks: The probability of a genetic disease recurring in a subsequent birth is known as the recurrence risk. Genetic defects may be detected prenatally by analyzing fetal cells obtained through amniocentesis, chorionic villi sampling, or maternal circulation.424–426 Genetic diagnosis of retinoblastoma has been successful in certain instances. For example, presymptomatic blood testing of RB1 carrier status in 10 persons with a family history of the disease was carried out.426 DNA samples were obtained prenatally by chorionic villi sampling, from cord blood samples, or from venipuncture of neonates. Bilateral tumors developed in one child who was shown to carry the mutant RB1 gene; they did not develop in six other children who did not carry the mutant RB1 gene.
  4. DNA diagnosis in presymptomatic patients: Intragenic and flanking DNA markers are useful for the presymptomatic diagnosis of diseases. For example, 14 families containing 23 asymptomatic subjects at a 50% prior risk of von Hippel-Lindau disease were analyzed. By combining age-related and DNA-based risk information and DNA analysis using markers flanking the von Hippel-Lindau disease gene, the carrier risk for 11 of these 23 individuals was reduced to less than 2%.427 DNA diagnosis before the clinical onset of symptoms and signs is particularly important in diseases such as POAG, in which early detection may offer a significant benefit in terms of patient management.
  5. Management options: Once the result of genetic analysis is available, patients and families will often need to make difficult decisions. If the genetic prognosis is unfavorable, a couple may decide to refrain from childbearing to avoid the risk of having an affected offspring. There are many factors that influence patients' and families' decisions with regard to the degree of risk that parents are willing to accept, including personality, experience, religious background, moral convictions, and the burden of care imposed by the clinical condition. Earlier detection of patients with ocular tumors such as retinoblastoma may significantly improve their visual prognosis by allowing clinicians to detect and treat the tumors while they are small, which may lead to improved systemic prognosis as well.
  6. Future follow-up and supportive services: Ophthalmologists should inform families about promising new research regarding the diseases concerned, and patients and families should be afforded the opportunity to participate in research protocols.

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Genetic disease may be treated with diet modification, as demonstrated by the classic example of phenylketonuria. The characterization of genes and gene products involved in ophthalmic diseases is offering exciting prospects in the design of therapeutic drugs. Human gene therapy currently is being tested in selected, though nonophthalmologic, diseases.428,429 The goal of human gene therapy is either (1) to replace defective copies of genes via gene-transfer techniques, such as retroviral or adenoviral vectors; or (2) to inhibit specific genes with the use of suppressive elements, such as the antisense technology. Though there are still many important questions that need to be answered about this technology,428,429 human gene therapy has the potential to revolutionize medicine, including ophthalmology.


The future of molecular ophthalmology holds a bright promise. Recently, there have been many exciting developments with important implications for the future of this field, some of which are discussed below.

Disease Reclassification Based on Molecular Pathogenesis

An emerging pattern in the study of the molecular genetics of ocular diseases is the recognition of the genotypic and phenotypic heterogeneity in these diseases. For example, we have seen examples of both allelic and nonallelic heterogeneities in retinitis pigmentosa. Thanks to advances in the molecular characterization of ocular diseases, we are recognizing not only distinctly different disease entities based on molecular studies within what previously was believed to be one disease, but also new associations between clinically disparate entities. As a result, both clinical “lumping” as well as “splitting”91 are required for improved clinical classification and management of these diseases. Important phenomena such as ocular gene sharing are increasingly being recognized. For example, X-linked FEVR and Norrie's disease are allelic.54 Gene sharing is also demonstrated in lens crystallin, which has been found not only to be responsible for lens refraction, but also to be involved in metabolic enzymatic activities related to cellular stress.430 Such gene sharing phenomena suggests unique targets for gene therapy.

Allelic and Nonallelic Heterogeneities and Implication for Gene Tracking

Allelic and nonallelic heterogeneities are commonly observed in ophthalmic diseases. As we have seen in the case of retinoblastoma, various mutations in RB1 (allelic heterogeneity) (see Fig. 17) are involved in tumorigenesis. The presence of nonallelic heterogeneity in certain diseases, however, may be a problem in terms of gene tracking. For example, ADRP appears to involve at least 10 different loci (see Table 3). To improve the chromosomal resolution of linkage studies to ultimately identify the disease gene, one must pool together different pedigrees to achieve statistical significance. Such an effort, however, may mislead linkage studies because the disease in these families may be due to defects in different genes (nonallelic heterogeneity). This has contributed to the fact that, at present, none of the retinitis pigmentosa loci identified by linkage study has led directly to gene identification. This is in contrast to cystic fibrosis, for example, in which the disease is caused mainly by a defect in one gene; accumulation of data from a large number of pedigrees has led directly to gene identification.1 In the present gene-tracking effort for Stargardt's disease, one must be aware of the presence of nonallelic heterogeneity in pooling together families for further improvement of resolution for the linkage study, since Stargardt's disease appears to involve at least three genetic loci.305–307

New Choices of Candidate Genes

The molecular characterization of ocular disease processes may provide new choices of candidate genes. For example, the elucidation of the homologous nature of the choroideremia gene and the rat Rab geranylgeranyl transferase gene155 not only suggests that the pathogenic basis of choroideremia may be related to defects in membrane transport of protein and signal transduction systems,155 but also raises the possibility that the genes encoding a family of well-characterized G-proteins may be considered candidate genes for retinal degeneration.

Identification of Important Chromosomal Regions for Ophthalmic Diseases

Certain chromosomal regions appear to be particularly critical in that they contain multiple important genes responsible for ocular diseases. For example, the chromosomal region near Xp11.3 appears to be important for retinal function because it contains one locus for congenital stationary night blindness,176–178 two loci for X-linked retinitis pigmentosa (RP2179–183 and RP3183–186), one locus for Norrie's disease, one locus for ocular albinism type 2,96 and one locus for X-linked FEVR.206 There is evidence for an additional gene related to myopia in this region.96 The biochemical and clinical implication of such closely situated ocular disease genes are only beginning to be appreciated.

Recognition of Common Pathways for Diseases and Implication for Therapy

Recognition of bottle-neck steps in pathogenic processes, such as the apoptosis in retinal degeneration, suggests exciting targets for gene therapy. It appears likely that photoreceptor degenerative processes, irrespective of their various initiating gene mutational processes, may proceed through a common apoptotic pathway. By inhibiting such a bottle-neck (") step, one may be able to design effective therapeutic drugs to retard or even prevent retinal degeneration.

Data Banking for Mutations and Clinical Phenotypes: Implication for Genetic Counseling

Accumulation of data concerning the relationship between gene mutations and corresponding clinical phenotypes may have a significant impact on the clinical management of patients with the diseases. For example, more than 70 DNA mutations have been found in the rhodopsin gene in patients with ADRP.14,20,24,47,62–92,335a A systematic effort in documenting the relationships between genotypes and phenotypes will no doubt have an important benefit to patients with regard to their visual prognosis.

The Study of Gene Function and Gene Expression Regulation

The study of gene expression regulation in ocular disease processes is increasingly becoming a focus of research in the frontier of molecular ophthalmology. We have spent the last decade cloning and identifying disease-causing genes, and we are likely to focus more effort in the upcoming decade on the next—albeit more difficult—step of studying the regulation and biologic function of these ocular disease genes. For example, the study of regulatory mechanisms of growth-regulating activity of the retinoblastoma protein is uncovering new and unexpected biologic functions of what was previously thought as just a tumor-suppressor gene.359 Studies in the regulation of visual pigment gene expression using human genetics and transgenic mouse technology have proved insightful.431 These and other studies in gene-expression regulation are likely to benefit from the development of new in vitro and in vivo technologies.432

New Strategies for Therapy

The discovery of the molecular defects involved in ocular diseases will provide a basis for new strategies of treatment. For example, targeting the gene regulation of aqueous humor production may provide an exciting new approach to glaucoma therapy.433 Elucidation of the molecular mechanisms of retinal photoreceptor degeneration may help provide rescue strategies, such as gene therapy, administration of growth or trophic factors, dietary supplementation (e.g., vitamin A), protection from environmental insult, and retinal pigment epithelium transplantation.434

Early Diagnosis and Impact on Clinical Management

The identification of gene defects in ocular diseases will have a significant impact on clinical management, particularly with regard to diseases such as POAG that have insidious clinical onset and in which earlier detection and treatment may significantly alter the visual prognosis. Detection of DNA mutations in patients predisposed to this disease and institution of early therapy before the onset of any optic nerve damage will no doubt revolutionize this field.

Gene Therapy

Gene therapy, still in its infancy, has a remarkable potential. One should be hopeful that with the exciting new developments in molecular biology, a new era has arrived in the field of ophthalmology that promises new methods of disease classification and treatment.

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