Janey L. Wiggs
The study of inherited forms of glaucoma has led to exciting advances. An aspect of the molecular genetic approach that has been particularly important to glaucoma research is that only DNA (usually obtained from a simple peripheral blood sample) from an affected individual is required. Biochemical approaches to the study of glaucoma have been hindered by the inability to sample unaltered human tissue, specimens taken from affected patients undergoing glaucoma surgery typically have been exposed to numerous medical and laser treatments that could obscure the initial abnormalities responsible for the disease. Genetic analysis can avoid these problems because the investigation of the disease process is at the DNA level, and the actual diseased tissue, or even knowledge about how the disease affects a particular tissue, is not necessary. The study of genes responsible for glaucoma will lead to the identification of proteins that participate in the disease without a requirement for direct access to the diseased tissue.
For many years, a family history of glaucoma has been recognized to be an important risk factor for this disease.[1,2] Glaucoma can be inherited as a Mendelian single gene disorder, caused by a single gene defect, or as a complex trait that is the result of the interactions of multiple genes and environmental factors. In general, the early onset forms of glaucoma are inherited as Mendelian autosomal dominant or recessive traits, while the adult onset forms of the disease are inherited as complex traits. Genes that predispose to glaucoma may influence the increase in intraocular pressure or degeneration of the optic nerve or both.
The types of glaucoma inherited as Mendelian traits include, juvenile open-angle glaucoma (autosomal dominant),[3-10] congenital glaucoma (autosomal recessive),[11-12] developmental glaucomas (Rieger's syndrome and aniridia; autosomal dominant),[13-16] and pigmentary glaucoma (autosomal dominant).[17-21] The current genes and loci identified for these and other forms of glaucoma are shown in Table 193.1.
TABLE 193.1 -- Chromosomal Location of Genes Responsible for Different Forms of Glaucoma
|
Chromosome Location |
Condition |
Locus (Gene) |
Inheritance Pattern |
Reference |
|
1q23 |
Primary open-angle glaucoma |
GLC1A |
Juvenile: AD |
9 |
|
Juvenile and adult onset |
(MYOC) |
Adult: complex |
23 |
|
|
1p36 |
Congenital glaucoma |
GLC3B |
AR |
66 |
|
2p21 |
Congenital glaucoma |
GLC3A |
AR |
12 |
|
(CYP1B1) |
59 |
|||
|
2cen-2q13 |
Primary open-angle glaucoma, Adult onset |
GLC1B |
AD |
47 |
|
3q21-24 |
Primary open-angle glaucoma, Adult onset |
GLC1C |
AD |
48 |
|
4q25 |
Rieger syndrome |
RIEG1 |
AD |
14 |
|
(PITX2) |
77 |
|||
|
5q22 |
Primary open-angle glaucoma, Adult onset |
GLC1G |
AD |
52 |
|
(WDR36) |
Complex |
52 |
||
|
6p25 |
Iridodysgenesis |
IRID1 |
AD |
16 |
|
(FOXC1) |
78 |
|||
|
7q35 |
Primary open-angle glaucoma, adult onset |
GLC1F |
AD |
51 |
|
7q35-q36 |
Pigment dispersion syndrome |
GPDS1 |
AD |
17 |
|
8q23 |
Primary open-angle glaucoma, adult onset |
GLC1D |
AD |
49 |
|
9q22 |
Primary open-angle glaucoma, juvenile onset |
GLC1J |
AD |
40 |
|
9q34 |
Glaucoma associated with nail-patella syndrome |
(LMX1B) |
AD |
81 |
|
10p15-p14 |
Primary open-angle glaucoma, adult onset; low-tension glaucoma |
GLC1E |
AD |
50 |
|
(OPTN) |
53 |
|||
|
11p |
Nanophthalmos |
NNO1 |
AD |
83 |
|
11p13 |
Aniridia |
AN2 |
AD |
13 |
|
(PAX6) |
92 |
|||
|
13q14 |
Rieger syndrome |
RIEG2 |
AD |
15 |
|
14q11 |
Primary open-angle glaucoma, adult onset |
GLC1L |
Complex |
55 |
|
15q11-q13 |
Primary open-angle glaucoma, adult onset |
GLC1I |
Complex |
56 |
|
20p12 |
Primary open-angle glaucoma, juvenile onset |
GLC1K |
AD |
40 |
|
AD, autosomal dominant; AR, autosomal recessive. |
JUVENILE-ONSET PRIMARY OPEN-ANGLE GLAUCOMA
Primary juvenile open-angle glaucoma is a rare disorder that develops during the first two decades of life. Affected patients typically present with a high intraocular pressure that ultimately requires surgical therapy. Characteristic features include a high incidence of myopia and normal-appearing angle structures. These patients do not have a Barkan membrane covering the angle or findings associated with anterior segment dysgenesis syndromes.[7,10] One histopathologic study of 10 patients has suggested the presence of a thick compact tissue on the anterior segment of Schlemm's canal.[22] Other specific ocular or systemic abnormalities have not been identified in these patients.
Juvenile glaucoma can be inherited as an autosomal dominant trait. Large pedigrees have been identified and used for genetic linkage analysis. One gene responsible for this condition was initially located on chromosome 1q23 (GLC1A), and the gene was identified as the MYOC gene coding for the protein myocilin. (In early studies the gene was also called TIGR for trabecular meshwork glucocorticoid response protein).[23,24] The protein contains a leucine zipper (found in regulatory sequences and in proteins capable of dimerization) and a domain that has homology to human neuronal olfactomedin. Mutations in this gene are found in 3-5% of adult-onset POAG (primary open-angle glaucoma) patients and in 8-20% juvenile-onset POAG patients.[25,26] Different mutations are associated with juvenile and adult glaucoma. In particular the most common mutation associated with adult glaucoma is a stop codon, while all the mutations associated with juvenile glaucoma are missense mutations.[27] Some of the mutations typically associated with adult glaucoma can cause more severe earlier-onset glaucoma when found in combination with DNA sequence variants in the CYP1B1 gene.[28] This result may indicate that these two proteins affect the same biochemical pathway. Interestingly, most of the mutations associated with glaucoma identified to date have been found in the portion of the gene coding for the olfactomedin domain.[29]
The role of the normal myocilin protein in the outflow pathways is not well understood. Most interestingly, one individual who is homozygous for a nonsense mutation occurring at codon 46 does not have glaucoma.[30] This individual probably does not have any functional myocilin, making the normal role of the protein in the trabecular outflow pathways unclear. The normal protein has been detected in the extracellular matrix[31,32] suggesting it is secreted from the cell, and some studies have indicated that the mutant forms of the protein are not secreted.[33,34]
The underlying genetic mechanism responsible for myocilin associated disease appears to be either a 'gain of function' mechanism or a 'dominant negative' mechanism. The absence of disease in an adult human who is hemizygous for MYOC and in mice with targeted disruption of the MYOC gene provide support for this hypothesis.[35,36]
Studies have shown that the mutant forms of the protein result in translational pausing and in vitro form a precipitate.[37,38] Recent evidence demonstrates that the disease-causing myocilin mutants are misfolded, and are highly aggregation-prone causing large aggregates of misfolded protein to accumulate in the endoplasmic reticulum.[39] Alternatively, mutant forms of myocilin may prevent the processing and secretion of other proteins that are necessary for the normal function of the trabecular outflow pathways.
Recently, a whole genome linkage study for juvenile open-angle glaucoma has been completed and has identified two new chromosome regions that are likely to contain novel genes responsible for this form of the disease (GLC1J, GLC1K).[40]
ADULT-ONSET POAG
POAG of adult onset is the most common form of glaucoma, affecting 7-8 million Americans. Previous studies suggest that susceptibility to POAG is inherited. The prevalence of POAG in first-degree relatives of affected patients has been documented to be as high as 7-10 times that of the general population.[41] Patients affected by POAG are more likely to have an increase in intraocular pressure in response to dexamethasone eye drops, and this trait has been shown to be inherited.[42] Several twin studies have suggested a high concordance of glaucoma between monozygotic twins, consistent with a significant genetic predisposition to the disease.[43-45] The higher prevalence of POAG among African Americans compared with whites may reflect an underlying genetic difference in susceptibility to this disorder.
It is likely that multiple genes (independently or in combination) are responsible for the heritability of POAG. The variability in the age of onset of the disease, the apparent incomplete penetrance of the condition in some pedigrees, and the prevalence of the disease all suggest that more than one gene may be responsible for the disorder. Patients affected by POAG also vary with respect to the relationship between increased intraocular pressure and deterioration of the optic nerve. These observations are consistent with the conclusion that POAG is not inherited as a simple single gene disorder but as a complicated 'complex trait'.[46]
The reduced penetrance and genetic heterogeneity typical of complex traits can make gene mapping studies for POAG difficult. However, using large affected pedigrees and Mendelian linkage approaches, seven glaucoma gene loci (GLC1A-G) have been identified.[9,47-52] Three of the responsible genes have been identified. The MYOC gene (GLC1A) as described above primarily causes elevated pressure[23,26] and the OPTN gene (GLC1E) coding for the protein optineurin appears to contribute to disease in familial low-tension glaucoma[53] (discussed later). Recently DNA sequence changes have been identified in the WDR36 gene located within the chromosomal region defined as GLC1G.[52] Mutations in this gene do not appear to be an independent cause of glaucoma, but may influence the severity of the disease in an affected person.[54] Sibpair-based whole genome analyses using typical late-onset families have also identified chromosomal regions likely to contain POAG susceptibility genes, including 14q11,[55] 15q12,[56] 2q,[57] and 10p.[57]
CONGENITAL GLAUCOMA
Congenital glaucoma is a genetically heterogeneous condition that is typically apparent at birth but may go undiagnosed until the patient is 3 years of age. Because of the flexibility of the sclera in babies, the elevation of intraocular pressure associated with this condition causes buphthalmos. This finding is usually the indication that the child is affected. Increased intraocular pressure in eyes affected by congenital glaucoma is probably the result of abnormal development of the anterior segment of the eye. Specifically, in many cases of congenital glaucoma, a membrane presumably obstructing the path of aqueous humor can be visualized.
Congenital glaucoma is inherited as an autosomal recessive trait, and is prevalent in countries where consanguinity is common.[58,59] Defects in the gene coding for CYP1B1, a protein that is a member of the cytochrome P450 (CYP) family have been detected in individuals affected with congenital glaucoma from a number of different countries including Saudi Arabia, Turkey, Slovakia (gypsies), Japan, and more heterogeneous populations such as the United States and Brazil. Missense mutations, deletions and insertions have been identified in affected individuals. Most of the missense mutations occur in the highly conserved 'hinge' region of the protein.[60] The frequent occurrence of deletions and insertions suggest that a loss of protein function is the underlying genetic mechanism. Recurrent mutations have been found in the gene in patients from varied ethnic backgrounds. Recent work indicates the recurrent mutations are on ancient chromosomes that have a common haplotype.[61]
Human CYP 1B1 is the product of the CYP1B1 gene and is a key enzyme in the metabolism of 17beta-estradiol. Alteration of metabolism of estrogens, and related compounds may be the basis for the abnormal ocular development caused by mutation of CYP1B1.[62]
Most of the mutations in CYP1B1 result in severe glaucoma, however, at least one mutation, the SNFdel may be associated with milder disease.[61,63] Tyrosinase activity may also modify the severity of the anterior segment defects caused by CYP1B1 in mice,[64] however this effect of tyrosinase has not been found in humans.[65] Co-segregation of MYOC gene defects (discussed earlier) may also be a factor in the variable expression of the phenotype caused by defects in this gene.[28]
Linkage studies have identified at least one other chromosomal region (1p36) that is likely to harbor a gene for congenital glaucoma.[66] In addition, autosomal dominant forms of congenital glaucoma have been identified.[67]
PIGMENT DISPERSION SYNDROME AND PIGMENTARY GLAUCOMA
The pigment dispersion syndrome is associated with the development of pigmentary glaucoma. Pigment dispersion is a common disorder in young adults. Studies have shown that up to 2-4% of the white population between the ages of 20 and 40 years may be affected by this disorder. Characteristic features of this syndrome include a loss of iris contour and loss of pigment granules from the iris. The released pigment is deposited on the structures of the anterior segment of the eye, including the trabecular meshwork. Although it is generally accepted that the dispersed iris pigment contributes to the development of glaucoma in affected patients, the pathogenesis of pigmentary glaucoma remains unknown.
Pigment dispersion has been shown to be inherited as an autosomal dominant trait, suggesting that specific gene defects may be responsible. One locus for this syndrome has been located on chromosome 7q35-36.[17] The responsible gene has yet to be isolated. Because of the high prevalence of this condition, it is likely that more than one gene may be responsible for this disorder.
A mouse model of pigment dispersion and pigmentary glaucoma exists. DBA2 mice develop a pigment dispersion-like syndrome associated with glaucoma (John et al, 1998). Two genes in the mouse contribute to the disease: TYRP1 (Tyrosinase-related protein 1) and Gpnmb (Glycoprotein NMB).[68] Both of these genes are involved in pigment production and/or stabilization of melanosomes. Neither of these genes contribute to the disease in humans.[69]
PSEUDOEXFOLIATION SYNDROME
Pseudoexfoliation is a condition characterized by a distinctive fibrillary degeneration of the lens capsule. This material, although most easily visualized on the lens capsule, is actually present throughout the anterior segment of the eye and has been found to exist systemically in the skin and blood vessels. Pseudoexfoliation is associated with a severe high-pressure glaucoma causing rapid deterioration of the optic nerve. Although the biochemical defect responsible for this disease is unknown, basement membrane alterations have been observed in pathology specimens taken from affected individuals, suggesting that alterations of the protein constituents of the basement membranes may be involved in this process.[70] Other systemic abnormalities that may be associated with pseudoexfoliation include homocysteine elevation[71] and abdominal aortic aneurysm formation.[72]
The distinctive geographic distribution of pseudoexfoliation is most consistent with founder effects caused by inheritance of genes responsible for this condition. A high prevalence of this disease is found in Scandinavia, Russia, Nova Scotia, Scotland, the northeastern United States, Saudi Arabia, Greece and in the African Bantu. The disease has a low prevalence in the Eskimo population and in Germany, the United Kingdom, and the southern United States. Pedigrees affected by pseudoexfoliation have been reported.[73] The results of these studies suggest that the disease is inherited as a dominant trait with incomplete penetrance. The degree of genetic heterogeneity of the condition remains unknown. To date, loci harboring genes responsible for this condition have not been located in the human genome.
ANTERIOR SEGMENT DYSGENESIS SYNDROMES
Glaucoma can result from abnormal development of the anterior segment of the eye. Specific disorders affecting humans are Axenfeld-Rieger syndrome, Aniridia, and the anterior segment dysgenesis syndrome. These diseases are may be associated with systemic defects involving the teeth, facial bones, heart, and umbilicus. The genes responsible for these disorders participate in the regulation of gene expression during development (Table 193.2).[74,75] These disorders are all inherited as autosomal dominant traits, and in general the DNA defects lead to loss of function of the protein and haploinsufficiency.[76]
TABLE 193.2 -- Genes Associated with Anterior Segment Dysgenesis and Glaucoma
|
Gene |
Chromosome Location |
Features |
Mouse Model |
Human Disease |
Reference |
|
PITX2 |
4q27 |
Paired-bicoid homeodomain |
Yes |
Anterior segment dysgenesis, umbilical, and teeth abnormalities |
77 |
|
FOXC1 |
6p25 |
Forkhead domain |
Yes |
Anterior segment dysgenesis, teeth abnormalities, cardiac abnormalities |
76, 78 |
|
LMX1B |
9q34 |
Lim domain |
Yes |
Anterior segment abnormalites, nail-patella syndrome, glomerular nephropathy |
81 |
|
PAX6 |
11p13 |
Paired domain |
Yes |
Aniridia |
79 |
Loci for Rieger's syndrome have been located on chromosomes 4q25,[14] and 13q14.[15] The PITX2 gene has been identified as the chromosome 4 gene[77] while the chromosome 13 has yet to be identified. Typical clinical findings may include posterior embryotoxon, iris hypoplasia, iridocorneal adhesions, and corectopia. A syndrome of anterior segment dysgenesis and iris hypoplasia is caused by mutations in the FOXC1 gene, coding for a transcription factor containing a fork-head domain.[78] PAX6 is the gene responsible for aniridia[79] and mutations in this gene have also been found in patients with Peter's anomaly and autosomal dominant stromal keratitis.[80] Mutations in LMX1B causing nail-patella syndrome may also be associated with glaucoma.[81]
Nanophthalmos results from abnormal growth of the eye, causing a short axial length and increased risk of angle-closure glaucoma. One gene, VMD2 has been associated with a condition causing nanophthalmmos and autosomal dominant vitreoretinochoroidopathy,[82] one chromosome loci containing a gene responsible for primary nanophthalmos has been identified.[83]
LOW-TENSION GLAUCOMA
In some patients degeneration of the optic nerve occurs even though the intraocular pressures are in the normal range. This type of glaucoma is called 'low-tension' or 'normal-tension' glaucoma, and is thought to represent a subtype of adult-onset POAG. The clinical appearance of the optic nerve in low-tension glaucoma and in primary optic neuropathies is very similar. Polymorphisms in the gene OPA1responsible for an autosomal dominant form of primary optic neuropathy may be associated with low-tension glaucoma in some cases.[84]
Low-tension glaucoma has also been associated with mutations in a novel gene, OPTN.[53] The protein, optineurin, may participate in the TNF? signaling pathway. TNF? may be one factor that can induce apopotosis in retinal ganglion cells in patients with low-tension glaucoma and in patients with POAG.[85,86] It has been speculated that the optineurin protein may function to protect the optic nerve from TNF?-mediated apopotosis, and that the loss of function of this protein may decrease the threshold for ganglion cell apopotosis in patients with glaucoma.
Missense mutations in optineurin are an infrequent cause of low-tension glaucoma.[87] Surprisingly, mutations in this gene do not appear to significantly contribute to the optic nerve degeneration that is a component of typical high pressure POAG.[88]
Studies of lymphocytes in patients with low-tension glaucoma has also identified several genes with altered expression including p53.[89] Abnormal regulation of apoptosis may be one mechanism responsible for low-tension glaucoma. Possibly genes that predispose to low-tension glaucoma may also contribute to nerve degeneration in patients with POAG associated with increased intraocular pressure.
FUTURE DIRECTIONS
The identification of genes causing glaucoma is just an initial step in understanding the pathophysiology of the disorder. Once genes responsible for glaucoma are found, the normal biologic function of the protein products of these genes must be established. To understand the normal role of the genes responsible for glaucoma, the specific proteins and classes of proteins they code for, when and where the genes are expressed, and how the expression is regulated must be determined. Current treatment for glaucoma is directed toward the regulation of aqueous humor formation by the ciliary body and increased outflow of aqueous humor through the trabecular meshwork or alternative pathways created by surgical procedures. Current therapy does not actually treat the cause of the disease because the cause is unknown. Determining the functions of the normal and abnormal protein products of genes responsible for glaucoma will identify the processes that can result in this disease and will suggest novel treatments based on the specific disease mechanisms. In addition to the development of new medical treatments for glaucoma, isolating genes responsible for the disease may also lead to the development of gene therapy that could effectively replace damaged genes and correct the underlying defects.
Isolating genes responsible for glaucoma will also lead to new methods of diagnosing the condition based on the DNA sequence changes that result in defective genes and protein products. Such DNA-based diagnostic tests can identify individuals at risk for the disease before any visual deterioration has occurred.
Little is known about how an abnormal gene product results in a glaucoma phenotype, and whether different mutations in the same gene can explain phenotypic variability. The identification of glaucoma-causing genes will allow the opportunity to determine whether the function of these genes and their products is influenced by the action of other genes or environmental factors, or both, that can modify the disease phenotype.
The identification of genes and loci involved in disease enables studies to evaluate the clinical features of the disorder with respect to the molecular information. It will be possible to determine whether cases of glaucoma caused by a specific gene share common features that can be recognized clinically. Similarly, it will be possible to determine whether molecular subclasses of disease respond similarly to specific treatment modalities. The combined knowledge from genetic and clinical studies will lead to new methods of diagnosis and treatment that will improve the prognosis and quality of life of affected individuals.
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