|
REVIEW ARTICLE |
|
Year : 2010 | Volume
: 3
| Issue : 2 | Page : 51-59 |
|
|
Gene therapy in glaucoma-part 2: Genetic etiology and gene mapping
Mohamed Abdel-Monem Soliman Mahdy
Department of Ophthalmology, Rusatq Hospital, Sultanate of Oman, and Al-Hussein University Hospital, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
Date of Web Publication | 9-Jun-2010 |
Correspondence Address: Mohamed Abdel-Monem Soliman Mahdy Department of Ophthalmology, Rusatq Hospital, Post Box: 2, Postal Code: 329 Rustaq, Sultanate of Oman
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0974-620X.64227
Abstract | | |
Glaucoma diagnosis, identification of people at risk, initiation of treatment and timing of surgical intervention remains a problem. Despite new and improving diagnostic and therapeutic options for glaucoma, blindness from glaucoma is increasing and glaucoma remains a major public health problem. The role of heredity in ocular disease is attracting greater attention as the knowledge and recent advances of Human Genome Project and the HapMap Project have made genetic analysis of many human disorders possible. Glaucoma offers a variety of potential targets for gene therapy. All risk factors for glaucoma and their underlying causes are potentially susceptible to modulation by gene transfer. The discovery of genes responsible for glaucoma has led to the development of new methods of Deoxyribonucleic acid (DNA)-based diagnosis and treatment. As genetic defects responsible for glaucoma are identified and the biochemical mechanisms underlying the disease are recognized, new methods of therapy can be developed. It is of utmost importance for the ophthalmologists and glaucoma specialists to be familiar with and understand the basic molecular mechanisms, genes responsible for glaucoma and the ways of genetic treatment. Method of Literature Search The literature was searched on the Medline database, using the PubMed interface. Keywords: Gene therapy, genetic diagnosis of glaucoma, glaucoma
How to cite this article: Mahdy MA. Gene therapy in glaucoma-part 2: Genetic etiology and gene mapping. Oman J Ophthalmol 2010;3:51-9 |
Article Outline | |  |
- Genetic Etiology of Glaucoma
- Genes Associated with Forms of Glaucoma with Mendelian Inheritance
A. Childhood Glaucoma
- Congenital Glaucoma
- Anterior Segment Dysgenesis Syndromes
- Axenfeld-Rieger,
- Nail-patella Syndrome,
- Aniridia and PAX6 Gene
B. Primary Open -Angle Glaucoma (POAG)
I. Genetic Loci for POAG
- GLC1A (TIGR/Myocilin)
- GLC1B
- GLC1C
- GLC1D
- GLC1E
- GLC1F
- GLC1G
- GLC1J, GLC1K and other loci
II. Candidate Genes Causative of POAG
III. Genes Associated with POAG and Gene-gene Interaction
C. Pigment Dispersion Syndrome
D. Pseudoexfoliation Syndrome and Glaucoma
- Conclusion; Developing a Diagnostic Panel for Patients at Risk for Glaucoma
Introduction | |  |
Glaucoma is the 2 nd most common cause of blindness in the world as determined by the world health organization (WHO). In Oman the rate of glaucoma cases reported by ophthalmologists was 1.14/1000. 11.5% of estimated blindness in Oman was due to glaucoma. [1],[2]
The role of heredity in ocular disease is attracting greater attention as the knowledge and recent advances of Human Genome Project and the HapMap Project made genetic analysis of many human disorders possible (the Human Genome was completed in April 2003 and the International HapMap Project in 2005). [3],[4],[5]
The discovery of genes responsible for glaucoma is opening the possibility of new methods of DNA-based diagnosis and treatment. As genetic defects and biochemical mechanisms responsible for glaucoma are, new methods of therapy can be developed. In some cases, understanding the responsible biochemical abnormalities may indicate metabolites, either small molecules or enzymes that could be administered to correct the problem. Using new technologies, novel methods of diagnosis and treatment, based on the genetic defects responsible for glaucoma, will allow individuals at risk for the disease to be identified and successfully treated before irreversible damage to the nerve has occurred. [6]
As large numbers of patients with genetic ocular disease especially glaucoma are identified, public demands for prevention, treatment and counseling increase. Consequently ophthalmologists, like other medical specialists are expected to be familiar with the clinical manifestations, transmission patterns, diagnostic techniques, and therapeutic modalities of heritable disorders in their specialty. [7] In a previous article in the Oman Journal of ophthalmology, the basic mechanisms and molecular genetic had been described. In this context this article is written to further highlight the overview of gene therapy in glaucoma especially the genetic etiology and mapping in various type of glaucoma. [8]
Genetic Etiology of Glaucoma | |  |
Inheritance of glaucoma could be Mendelian autosomal-dominant (AD), autosomal recessive (AR) trait, or as a complex multifactorial trait. Early onset forms of the glaucoma usually inherited as AR trait, while adult onset forms of the disease exhibit a heritable susceptibility consistent with a complex multifactorial trait inheritance. Recent advances in genetic approaches had helped to define the underlying molecular events responsible for some mendelian forms of the disease and had identified the chromosome locations of genes that are likely to contribute to common complex forms. [9]
Genes associated with different forms of glaucoma can be detected in the human genome using both large affected pedigrees and standard linkage analysis. [9] The simplicity of genetic approaches had lead to substantial success and most of the genes currently known to be associated with various forms of glaucoma were identified using these methods [Table 1].
Relationship Between Different Clinical Forms of Glaucoma and Genetic Mendelian Inheritance | |  |
Typically, early-onset forms of glaucoma are inherited as mendelian dominant or mendelian-recessive traits. These include early-onset open angle glaucoma; [10],[11],[12] congenital glaucomas [13] developmental glaucomas including Rieger syndrome, [14],[15] glaucoma associated with nail patella syndrome, [16] and nanophthalmos, [17] and glaucoma associated with pigment dispersion syndrome. [18],[19] Adult onset forms of the disease usually inherited as a complex multifactorial trait.
Childhood Glaucoma | |  |
Congenital glaucomas
Primary congenital or infantile glaucoma (GLC3): Usually occurs in early childhood, within the first year of life, but may develop later up to 3 years of age. It is usually inherited as an autosomal recessive trait and is prevalent in countries where consanguinity is common. [20],[21] In patients with congenital glaucoma, the development of the anterior segment of the eye and aqueous humor outflow pathways is abnormal, causing high IOP. Using consanguineous pedigrees from Saudi Arabia and Turkey, defects in the cytochrome P4501B1 (CYP1B1) gene coding for a protein that is a member of the cytochrome P450 family were found in individuals affected with congenital glaucoma. Subsequently, mutations in this gene have also been found in patients from many other countries including those with more heterogeneous populations, such as the United States and Brazil. Sarfarazi et al.[22] mapped a locus for primary congenital glaucoma, GLC3A, to 2p21. Mutations in the gene for cytochrome P4501B1 (CYP1B1) were identified, and account for most cases of autosomal recessive congenital glaucoma, CYP1B1 could be the predominant cause of primary congenital glaucoma (PCG) in the Omani population (78%). [22],[23] Numerous cytogenetic reports indicate other chromosome regions that may harbor congenital glaucoma genes, and autosomal dominant forms of congenital glaucoma have been identified. [24] Mapping studies in eight families with congenital glaucoma have revealed a second locus, GLC3B, at 1p36. [25]
The cytochrome P450 (a product of the CYP1B1gene) participates in the metabolism of many compounds, including 17B-estradiol. Loss of protein function is probably the underlying genetic mechanism, as most of the mutations are deletions, insertions, or missense mutations occurring in highly conserved protein regions that are necessary for its function. [20],[26] It has been hypothesized that alterations in the metabolism of estrogens may be the basis for the ocular abnormalities associated with defects in this gene. [27] Most patients with congenital glaucoma caused by mutations in CYP1B1 have severe form of the disease. [21] Also, a cytochrome P450-dependent arachidonic acid metabolite inhibits Na+, K+-ATPase in the cornea and may regulate corneal transparency and aqueous humor production. [28]
Anterior segment dysgenesis syndromes
Linkage studies suggest that genes responsible for anterior segment developmental abnormalities are located on chromosomes 13q14, [15] 4p, [29] 16q, [30] and 20p. In mice, several genes have been suggested as responsible for ocular developmental defects leading to glaucoma, including Bmp4, Foxe3, and Tgfb2[31] [Table 2].
Axenfeld-Rieger's syndrome: These forms of congenital glaucoma are associated with abnormal development of the anterior segment of the eye. Axenfeld-Rieger syndrome More Details, is characterized by malformations of the anterior segment as well as systemic involvement (facial and dental abnormalities). When the systemic features are lacking, it is termed Rieger (or Axenfeld-Rieger) anomaly. Although Axenfeld-Rieger anomaly and Rieger syndrome share similar ocular features, they are distinct entities on the genetic level.
Axenfeld-Rieger anomaly, mapped to 6p25, is associated with mutations in the FKHL7 gene that codes a transcription factor containing a fork-head domain, the gene responsible is FOXC1.[14],[32] Initial localization of the RIEGl gene, responsible for Rieger syndrome, was aided by cases of 4q-deletion that also demonstrated the Rieger's phenotype. Then it was further narrowed the locus to the 4q27 region which contain the gene PITX2. RIEGl was found to be a homeobox gene (PITX2 gene), namely a gene containing a sequence of about 180 DNA base pairs that are highly conserved throughout evolution. [33] These genes are thought to play an important role in development. A second locus involved in the Rieger phenotype was mapped to 13q14. [15] It is interesting to note that a gene for iridogoniodysgenesis, distinct from FKHL7, but in close proximity to it was identified at the 6p25 locus. [32]
Defects in the FOXC1 gene are found in patients with anterior segment dysgenesis. [32],[34] Patients with defects in both of the PITX2 and FOXC1 genes may also have associated systemic defects involving the teeth, facial bones, heart, and umbilicus.
Nail-patella syndrome is a systemic developmental disease associated with glaucoma caused by defects in LMX1B.[35] An autosomal-dominant form of nanophthalmos associated with vitroretinochoroidopathy has been shown to be caused by abnormalities in the VMD2 gene. [36] The genes responsible for these disorders participate in the regulation of gene expression during development, [37],[38] specifically in the development of the periocular mesenchyme, which includes neural crest- and cranial paraxial mesoderm-derived cells. [38] The DNA defects lead to loss of function of the protein and haploinsufficiency. [33],[34] Intrafamilial variability and variability in phenotypic expressivity may be caused by dosage effects or by the coexistence of other genes that can modify the expression of the trait.
Aniridia, nanophthalmos and PAX6 gene: Recent work suggests that PAX6 gene is a master control gene for eye formation throughout the animal kingdom, regulating the expression of other genes in time and space during embrygenesis. [39] Abnormalities in the PAX6 gene cause aniridia, as well as a spectrum of iris abnormalities related to glaucoma. [40] This gene, situated at 11p13, has been implicated in a heterogeneous group of anterior segment anomalies, including Peter's anomaly, autosomal dominant keratitis, congenital cataract with late onset corneal dystrophy, isolated foveal hypoplasia and aniridia. [41]
Primary Open-angle Glaucoma | |  |
Primary open-angle glaucoma (POAG) is the most common form of glaucoma, accounting for approximately 3% of visual impairment in white and 7.9% of African Americans. [42],[43] According to age of onset, POAG is divided into juvenile onset POAG (JOAG) and adult-onset POAG, with overlapping clinical presentations. JOAG, which develops before the age of 35, is a rare disorder that usually requires surgical therapy. [44],[4]5,[46] JOAG is typically inherited as an autosomal dominant trait, whereas adult-onset POAG is inherited as a complex trait. [45]
Genetic loci for primary open angle glaucoma
To date, at least 20 genetic loci for primary open angle glaucoma (POAG) have been reported [Table 3]. [47],[48] Among them, 11 chromosomal loci had been designated GLC1A to GLC1K by the HUGO Genome Nomenclature Committee ( www.gene.ucl.ac.uk/nomenclature ). Only 3 of them (GLC1A, GLC1J and GLC1K) contributed to JOAG, while the others contributed only to adult-onset POAG. [11],[49] The first gene identified as playing a role in Juvenile-onset POAG at the GLC1A locus mapped at chromosomal region 1q21-31. [11] Stone and colleagues identified mutations in a candidate gene that mapped to this region, in patients with the POAG. [50] The protein encoded by this gene had been independently characterized as "trabecular meshwork-induced glucocorticoid response protein" (TIGR) in trabecular meshwork cells in culture. [51] The same protein, named Myocilin, had also been localized to the outer segment cilium of photoreceptors by Kubota and colleagues. [52]
Only 3 causative genes are identified from these loci: Myocilin (MYOC), Optineurin (OPTN) and WD repeat domain 36 (WDR36), which together account for less than 10% of POAG. Only a portion of POAG follows Mendelian inheritance, and a considerable fraction results from a large number of variants in several genes, each contributing small effects. [53] The genetics of POAG are therefore complex. Both genetic and environmental factors are implicated in its etiology. For the 3 known POAG genes, only Myocilin (MYOC) is established as directly glaucoma causative, while the roles of Optineurin (OPTN) and WD repeat domain 36 (WDR36) are still unclear due to conflicting evidence. MYOC mutations account for 1.1%-4% of POAG, depending on the population. Up to 20% of patients with early-onset POAG and 3%-5% of patients with adult-onset POAG have defects in this gene. [54],[55] Some mutations are specifically associated with early onset disease, while others are more common in adult-onset patients. One study has suggested that heterozygous defects of the CYP1B1 gene can influence the severity of disease caused by mutations in MYOC.[56]
Single mutation in the TIGR gene may cause a variety of phenotypes from ocular hypertension (OHT) to (JOAG) to chronic open angle glaucoma (COAG). The variable expressivity in the JOAG and COAG patients may simply be a result of the age at which these candidates are affected. [57] 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 and the prevalence of the disease all suggest that more than one gene may be responsible for the disorder and POAG is not inherited as a simple single gene disorder but as a complicated "complex trait".
GLC1A (TIGR/Myocilin)
GLC1A is the 1 st locus linked to POAG phenotype. Most GLClA linked families have been characterized by a severe and aggressive form of open-angle glaucoma with an early onset, usually before age 40, peak IOPs greater than 30 mm Hg, and severe damage to the optic nerve. Many individuals required filtering procedure. [58],[59] It is inherited in an autosomal dominant fashion. The GLC1A region was originally mapped to chromosome 1q21-31. [11] Myocilin gene is identified as the gene mutated in this disorder. [50]
GLC1B
This is the second locus found to be linked to the POAG phenotype. [60] It is mapped to the centromeric portion of chromosome 2 (2 cen- q13). In contrast with GLClA families and individuals, those with the GLClB locus appear to be associated with a milder phenotype of adult onset POAG, lower peak-IOP, and older age of onset. Fifty percent of GLClB-affected individuals never have had a measured IOP higher than 22 mmHg whereas most of the remaining showed maximal elevations in the range of 22 to 30 mm Hg. The onset was usually in the late forties, with-a good response to medical therapy. This phenotype raises the question of whether normal tension glaucoma (NTG) is associated with this locus. If this is the case, the GLClB gene, once identified, may shed light on pathophysiologic mechanisms underlying the susceptibility of some optic nerves to damage at normal IOPs. No gene has yet been identified for this condition.
GLC1C
The GLC1C is mapped within to chromosome 3 within a locus chromosome 3q21-q24. Affected family members in the single pedigree shown to harbor the GLClC gene have glaucoma with high pressures, late onset, visual field loss and/or a cup disc ratio greater than normal and a moderate response to medication. [61] The average age of onset is over 40 years therefore classifying GLC1C as adult onset glaucoma. Although, apparently a rare mutation, the phenotype presented by GLClC patients is more typical of POAG as opposed to the younger onset of GLClA and the low IOPs of GLClB. Thus, it is possible that the GLClC gene will provide insight into the pathophysiologic mechanism of the more typical high IOP, late-onset, POAG.
GLC1D
The GLC1D locus was mapped to 8q23, this locus was identified through a linkage study of four generation North American family with adult-onset POAG. [62] The phenotype in this family appeared to be variable, with onset of visual field loss in middle age, followed by modest elevation of IOP and progression of the disease in older individuals. Little is known about the GLClD locus. To date, only a single family is known to harbor this 8q23 mutation. [61]
GLC1E
The GLC1E locus was mapped to 10p15-p14, this was identified in a large British family in which 15 of 46 family members were affected with NTG. [63] The age at diagnosis in this family varied between 23 and 65 years. The IOPs in the patients varied but were generally in the normal range with high cup disk ratios, visual field loss and changes of the optic nerve head. The candidate gene was recently identified as Optineurin (OPTN) based on its physical location in this region and its expression in retina. [64] It was the second gene identified for POAG.
GLC1F
Genome-wide scan of a large adult-onset POAG family spanning four generations mapped the GLC1F locus to 7q35-q36. [65] All 10 living patients in the family had POAG with grade IV gonioscopy, IOPs of 22 mm Hg or more, and vertical cup-disc ratios of 0.6 or more. Five of them had abnormal visual fields. Interestingly, a gene for pigment dispersion syndrome (PDS) was recently shown to occupy the same 7q35-36 locus. [19] One may only speculate on whether the same gene or different close-by genes are involved in these seemingly very different phenotypes.
GLC1G
In a genome-wide scan study, this new adult-onset POAG locus was mapped to 5q33-q35. The candidate gene for GLC1G was identified as WDR36. [66] It was the third POAG gene. Intriguingly, no coding variations of the WDR36 gene were found in 2 of the 7 GLC1G linked families, indicating a possibility of non-coding variations or of another POAG gene at GLC1G. [66] New data resulting from discrepancies between the genetic and physical maps positioned the upper boundary for this locus to 5q21.3. [66],[67] Although the function of the protein Product of this gene is unknown and the role of this protein in glaucoma remains to be confirmed, [68] prior studies suggest that it may participate in immune responses. Other studies had also suggested that glaucoma may be influenced by immune reactivity. [69] Interestingly, recent evidence suggests that mutations in the WDR36 gene are not an independent cause of glaucoma but may modify the severity of the disease in an affected person. [70]
GLC1J and GLC1K and other loci
Two JOAG loci were mapped to 9q22 and 20p12. [49] The locus on 9q22 was designated GLC1J. The 20p12 locus was designated GLC1K. Of the 15 families sufficient for haplotype analysis, haplotypes were consistent with GLC1J in 7 families, with GLC1K in 5 families, and with linkage to both loci in 3 families. [53]
Recent research mapped a novel JOAG locus to 5q22.1-q32 in a large autosomal dominant JOAG family from the Philippines. This 5-generations family had a total of 95 members, in which 22 were affected with JOAG. Complete ophthalmic examination was given to 27 family members, in which 9 were confirmed JOAG patients. [71] Also, a genome wide scan of 218 affected sibling pairs by using IOP as a continuous trait in linkage analysis identified two potential loci for IOP. [72]
Candidate genes causing POAG
In Caucasians about 2%-4% of POAG cases are due to MYOC mutations, [73] although it can be as high as 36% in JOAG families. [74] Mutations in OPTN, arguably the second POAG gene, were initially found in 16.7% of families with hereditary and adult onset POAG, and 12% of sporadic patients with POAG. The majority of them had IOP of less than 22 mm Hg. [64] Two subsequent studies on Caucasian POAG patients, one study involving 801 patients of variable age onsets [75] and one involving 86 adult-onset patients, [76] reported no glaucoma causing mutations in OPTN. In 148 Japanese patients with NTG and 165 with HTG, again no specific glaucoma-causing mutations in OPTN were identified. [77] The third gene for POAG was characterized as WDR36 at GLC1G. [66] In the original study, four mutations were found to be associated with more than 5% of all sporadic cases of POAG. [66]
Genes associated with POAG and gene-gene interaction
At least 16 POAG-associated genes have been reported from association studies [Table 4]. [78],[79] A couple of genes have been investigated in multiple association studies. However, conflicting findings were reported in different studies. The role of these genes in the etiology of POAG is still controversial. It is not clear yet whether the inheritance pattern of POAG is monogenic or complex polygenic. The following genes are an example of such genes;
Apolipoprotein E (APOE) had been reported to be a potent modifier gene for POAG. [79] The promoter polymorphism −219T>G was associated with increased optic nerve damage, while −491A>T interacted with a MYOC polymorphism, −1000C>G (MYOC.mt1), to increase IOP in POAG patients. The APOE e4 allele increased risk of NTG. [80]
Optic atrophy 1 (OPA1) was reported to associate with NTG in the British population. Two single nucleotide polymorphisms (SNPs) in the intron 8 of OPA1, IVS8 + 4C>T and IVS8 + 32T>C, were strongly associated with the occurrence of NTG but not with HTG. [81]
Cytochrome P4501B1 (CYP1B1) had been considered as a modifier gene for MYOC expression in JOAG patients. [82] Carriers with both mutations had early disease onset. Another study in a French population demonstrated CYP1B1 mutations were more prevalent in JOAG patients than controls. [83],[84]
Tumor protein p53 (TP53) was originally reported to be associated with POAG in a Chinese population. [85] The cytosine residue at codon 72 of the TP53 gene was significantly more common in POAG patients than controls.
Tumor necrosis factor (TNF) was associated with POAG. The promoter polymorphism −308G>A was significantly higher in POAG patients than in controls. A possible interaction between polymorphisms in the OPTN and TNF genes was identified to increase the POAG risk. [86] carriers with minor alleles of TNF/−863C>A, and OPTN/ c.603T>A were more common among POAG patients. These interactions between TNF and OPTN were found to worsen visual fields in POAG patients.
There is increasing evidences that the possible interaction between MYOC, OPTN and APOE might contribute to the development of POAG, indicating a polygenic etiology. [87]
Pigment Dispersion Syndrome | |  |
Approximately 50% of the individuals with clinical evidence of pigment dispersion syndrome will develop glaucoma. In humans the disease can be sporadic or inherited, with most pedigrees demonstrating autosomal-dominant inheritance patterns. [18],[19] In pigment dispersion syndrome, pigment granules from the iris pigmented epithelium are deposited on various ocular structures, including the trabecular meshwork. The disorder most frequently affects young myopic individuals. In 1981 Scheie and Cameron documented autosomal dominant inheritance in pigment dispersion syndrome. [88] Specific genes responsible for the human condition have not yet been identified; however, linkage studies suggest that 1 gene is located on chromosome 7q36. [19] Two loci for pigment dispersion syndrome phenotypes similar to human pigmentary glaucoma had been identified in mouse. The first identified locus linked to the pigment dispersion syndrome phenotype, PDS1, is located at 7q35-36. [19] A second locus, PDS2, was mapped to 18qll-q22. [89] Two genes in the mouse contribute to the disease: TYRP1 (Tyrosinase related protein 1) and Gpnmb (Glycoprotein NMB). Both of these genes are involved in pigment production and/or stabilization of melanosomes. [90] Neither of these genes contribute to the disease in humans.[91] Although, pigment dispersion syndrome is considered to be a secondary glaucoma, identification of the genes causing this condition may have a direct relationship with the pathogenesis of POAG.
Pseudoexfoliation and Pseudoexfoliative Glaucoma | |  |
Pseudoexfoliation syndrome (PEX) is a systemic disease, manifests in a proportion of affected individuals with elevated IOP and glaucomatous damage. Pseudoexfoliation is primarily a disease of the elderly and appears to have wide variation in its prevalence rate in different parts of the world. Despite that, it is rarely visible in a patient before age 55. Some two generation families with pseudoexfoliation have been described. [92] PEX high-pressure glaucomas account for half of all glaucomas in the eastern region of the Arabian peninsula including Oman. [93] A locus on chromosome 2 p16, [94] and maternal inheritance, perhaps suggestive of a mitochondria1 locus, have been reported. [95]
Genetic testing
Genetic testing is now available for humans. It tests 3 of more than 40 mutations for GLC1A, in addition to testing for a mutation of special interest, the MT1 promoter. Whether this mutation is associated with severity or prognosis for glaucoma is controversial and awaits further data. [96]
Developing a Diagnostic Panel for Patients at Risk for Glaucoma | |  |
One of the goals of disease gene discovery is the development of predictive diagnostic tests. For a disease such as glaucoma, where early treatment can be beneficial, diagnostic tests designed to identify individuals at risk for the disease can be particularly valuable. Current testing for glaucoma genes is limited to genes that are known to be associated with glaucoma and is primarily diagnostic, rather than prognostic. Except for specific mutations in the MYOC and OPTN genes, details regarding the predicted clinical course associated with a glaucoma gene mutation cannot be provided. Genotype-phenotype studies as outlined earlier will help define the prognostic aspects of currently known glaucoma gene mutations. Ultimately the goal is to discover a complete panel of genes that contribute to glaucoma and develop diagnostic and prognostic correlates for the mutations found in each gene. Such a panel would provide a mechanism to identify individuals at risk for the disease and initiate timely treatment before irreversible optic nerve degeneration and blindness occurs. [9]
References | |  |
1. | Khandekarl R, Zutshi R. Glaucoma in oman: a review. J Glaucoma 2006;15:271-3. |
2. | Khandekar R, Mohammed AJ, Negrel AD, Riyami AA. The prevalence and causes of blindness in the Sultanate of Oman: the Oman Eye Study (OES). Br J Ophthalmol 2002;86:957-62. |
3. | Human Genome Project. Available from: http://www.ncbi.nlm.nih.gov/sites/entrez?db=nucleotide . [last accessed on 2008 Feb 2]. |
4. | Guttmacher AE, Collins FS. Welcome to the genomic era. N Engl J Med 2003;349:996-8. |
5. | Hyman L, Klein B, Nemesure B, Wiggs J. Ophthalmic genetics: at the dawn of discovery. Arch Ophthalmol 2007;125:9-10. |
6. | Wiggs JL. Genetics and glaucoma. Ophthalmol Clin North Am 2000;13:481-8. |
7. | McKusick VA. Mapping and sequencing the human genome. N Engl J Med 1989;320:910-5. |
8. | Soliman Mahdy MA. Gene therapy in glaucoma-1; Basic mechanisms and molecular genetics. Oman J Ophthalmol 2010;3:2-6. |
9. | Wiggs JL. Genetic etiologies of glaucoma. Arch Ophthalmol 2007;125:30-7. |
10. | Johnson AT, Drack AV, Kwitek AE, Cannon RL, Stone EM, Alward WL. Clinical features and linkage analysis of a family with autosomal dominant juvenile glaucoma. Ophthalmology 1993;100:524-9. |
11. | Sheffield VC, Stone EM, Alward WL, Drack AV, Johnson AT, Streb LM, et al. Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Nat Genet 1993;4:47-50. |
12. | Richards JE, Lichter PR, Boehnke M, Uro JL, Torrez D, Wong D, et al. Mapping of a gene for autosomal dominant juvenile-onset open-angle glaucoma to chromosome Iq. Am J Hum Genet 1994;54:62-70. |
13. | Genĉνk A. Epidemiology and genetics of primary congenital glaucoma in Slovakia. Description of a form of primary congenital glaucoma in gypsies with autosomal-recessive inheritance and complete penetrance. Dev Ophthalmol 1989;16:76-115. |
14. | Mears AJ, Mirzayans F, Gould DB, Pearce WG, Walter MA. Autosomal dominant iridogoniodysgenesis anomaly maps to 6p25. Am J Hum Genet 1996;59:1321-7. |
15. | Phillips JC, del Bono EA, Haines JL, Pralea AM, Cohen JS, Greff LJ, et al. A second locus for Rieger syndrome maps to chromosome 13q14. Am J Hum Genet 1996;59:613-9. |
16. | Lichter PR, Richards JE, Downs CA, Stringham HM, Boehnke M, Farley FA. Cosegregation of open-angle glaucoma and the nail-patella syndrome. Am J Ophthalmol 1997;124:506-15. |
17. | Othman MI, Sullivan SA, Skuta GL, Cockrell DA, Stringham HM, Downs CA, et al. Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle- closure glaucoma maps to chromosome 11. Am J Hum Genet 1998;63:1411-8. |
18. | Paglinauan C, Haines JL, Del Bono EA, Schuman J, Stawski S, Wiggs JL. Exclusion of chromosome 1q21-q31 from linkage to three pedigrees affected by the pigment-dispersion syndrome. Am J Hum Genet 1995;56:1240-3. |
19. | Andersen JS, Pralea AM, DelBono EA, Haines JL, Gorin MB, Schuman JS, et al. A gene responsible for the pigment dispersion syndrome maps to chromosome 7q35-q36 [see comments]. Arch Ophthalmol 1997;115:384-8. |
20. | Bejjani BA, Lewis RA, Tomey KF, Anderson KL, Dueker DK, Jabak M, et al. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet 1998;62:325-33. |
21. | Bejjani BA, Stockton DW, Lewis RA, Tomey KF, Dueker DK, Jabak M, et al. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet 2000;9:367-74. |
22. | Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet 1997;6:641-7. |
23. | El-Gayar S, Ganesh A, Chavarria-Soley G, Al-Zuhaibi S, Al-Mjeni R, Raeburn S, et al. Molecular analysis of CYP1B1 in Omani patients with primary congenital glaucoma: a pilot study. Mol Vis 2009;15:1325-31. |
24. | Cohn AC, Kearns LS, Savarirayan R, Ryan J, Craig JE, Mackey DA. Chromosomal abnormalities and glaucoma: a case of congenital glaucoma with trisomy 8q22-qter/monosomy 9p23-pter. Ophthalmic Genet 2005;26:45-53. |
25. | Akarsu AN, Turacli ME, Aktan SG, Barsoum-Homsy M, Chevrette L, Sayli BS, et al. A second locus (GLC3B) for primary congenital glaucoma (Buphthalmos) maps to the 1p36 region. Hum Mol Genet 1996;5:1199-203. |
26. | Stoilov I, Akarsu AN, Alozie I, Child A, Barsoum-Homsy M, Turacli ME, et al. Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1. Am J Hum Genet 1998;62:573-84. |
27. | Jansson I, Stoilov I, Sarfarazi M, Schenkman JB. Effect of two mutations of human CYP1B1, G61E and R469W, on stability and endogenous steroid substrate metabolism. Pharmacogenetics 2001;11:793-801. |
28. | Schwartzman ML, Balazy M, Masferrer J, Abraham NG, McGiff JC, Murphy RC. 12(R)-hydroxyicosatetraenoic acid: a cytochrome- P450-dependent arachidonate metabolite that inhibits Na+, K -ATPase in the cornea. Proc Natl Acad Sci U S A 1987;84:8125-9. |
29. | Finzi S, Pinto CF, Wiggs JL. Molecular and clinical characterization of a patient with a chromosome 4p deletion, Wolf-Hirschhorn syndrome, and congenital glaucoma. Ophthalmic Genet 2001;22:35-41. |
30. | Ferguson JG Jr, Hicks EL. Rieger′s anomaly and glaucoma associated with partial trisomy 16q: case report. Arch Ophthalmol 1987;105:323. |
31. | Blixt A, Mahlapuu M, Aitola M, Pelto-Huikko M, Enerbδck S, Carlsson P. A forkhead gene, FoxE3 is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev 2000;14:245-54. |
32. | Mears AJ, Jordan T, Mirzayans F, Dubois S, Kume T, Parlee M, et al. Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 1998;63:1316-28. |
33. | Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW, Datson NA, et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 1996;14:392-9. |
34. | Nishimura DY, Searby CC, Alward WL, Walton D, Craig JE, Mackey DA, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 2001;68:364-72. |
35. | Hamlington JD, Jones C, McIntosh I. Twentytwo novel LMX1B mutations identified in nail patella syndrome (NPS) patients. Hum Mutat 2001;18:458. |
36. | Yardley J, Leroy BP, Hart-Holden N, Lafaut BA, Loeys B, Messiaen LM, et al. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Invest Ophthalmol Vis Sci 2004;45:3683-9. |
37. | Lines MA, Kozlowski K, Walter MA. Molecular genetics of Axenfeld-Rieger malformations. Hum Mol Genet 2002;11:1177-84. |
38. | Trainor PA, Tam PP. Cranial paraxial mesoderm and neural crest cells of the mouse embryo: co-distribution in the craniofacial mesenchyme but distinct segregation in branchial arches. Development 1995;121:2569-82. |
39. | Baulmann DC, Ohlmann A, Flόgel-Koch C, Goswami S, Cvekl A, Tamm ER. Pax6 heterozygous eyes show defects in chamber angle differentiation that are associated with a wide spectrum of other anterior eye segment abnormalities. Mech Dev 2002;118:3-17. |
40. | van Heyningen V, Williamson KA. PAX6 in sensory development. Hum Mol Genet 2002;11:1161-7. |
41. | Friedman JS, Walter MA. Glaucoma genetics, present and future. Clin Genet 1999;55:71-9. |
42. | Quigley HA. Number of people with glaucoma worldwide. Br J Ophthalmol 1996;80:389-93. |
43. | Quigley HA, Vitale S. Models of open-angle glaucoma prevalence and incidence in the United States. Invest Ophthalmol Vis Sci 1997;38:83-91. |
44. | Wiggs JL, Del Bono EA, Schuman JS, Hutchinson BT, Walton DS. Clinical features of five pedigrees genetically linked to the juvenile glaucoma locus on chromosome 1q21-q31. Ophthalmology 1995;102:1782-9. |
45. | Wiggs JL, Damji KF, Haines JL, Pericak-Vance MA, Allingham RR. The distinction between juvenile and adult-onset primary open-angle glaucoma. Am J Hum Genet 1996;58:243-4. |
46. | Johnson AT, Richards JE, Boehnke M, Stringham HM, Herman SB, Wong DJ, et al. Clinical phenotype of juvenile-onset primary open-angle glaucoma linked to chromosome 1q. Ophthalmology 1996;103:808-14. |
47. | Wiggs JL, Allingham RR, Hossain A, Kern J, Auguste J, DelBono EA, et al. Genome-wide scan for adult onset primary open angle glaucoma. Hum Mol Genet 2000;9:1109-17. |
48. | Allingham RR, Wiggs JL, De La Paz MA, Vollrath D, Tallett DA, Broomer B, et al. Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma. Invest Ophthalmol Vis Sci 1998;39:2288-95. |
49. | Wiggs JL, Lynch S, Ynagi G, Maselli M, Auguste J, Del Bono EA, et al. A genomewide scan identifies novel early-onset primary open-angle glaucoma loci on 9q22 and 20p12. Am J Hum Genet 2004;74:1314-20. |
50. | Stone EM, Fingert JH, Alward WL, Nguyen TD, Polansky JR, Sunden SL, et al. Identification of a gene that causes primary open angle glaucoma. Science 1997;275:668-70. |
51. | Nguyen TD, Chen P, Huang WD, Chen H, Johnson D, Polansky JR. Gene structure and properties of TIGR, an olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular meshwork cells. J Biol Chem 1998;273:6341-50. |
52. | Kubota R, Kudoh J, Mashima Y, Asakawa S, Minoshima S, Hejtmancik JF, et al. Genomic organization of the human myocilin gene (MYOC) responsible for primary open angle glaucoma (GLC1A). Biochem Biophys Res Commun 1998;242:396-400. |
53. | Fan BJ, Wang DY, Lam DS, Pang CP. Gene mapping for primary open angle glaucoma. Clin Biochem 2006;39:249-58. |
54. | Wiggs JL, Allingham RR, Vollrath D, Jones KH, De La Paz M, Kern J, et al. Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma. Am J Hum Genet 1998;63:1549-52. |
55. | Fingert JH, Hιon E, Liebmann JM, Yamamoto T, Craig JE, Rait J, et al. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 1999;8:899-905. |
56. | Vincent AL, Billingsley G, Buys Y, Levin AV, Priston M, Trope G, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 2002;70:448-60. |
57. | Morissette J, Cτtι G, Anctil JL, Plante M, Amyot M, Hιon E, et al. A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q. Am J Hum Genet 1995;56:1431-42. |
58. | Brιzin AP, Mondon H, Garchon HJ. Molecular genetics of open-angle glaucoma, moving from gene localization to predictive testing. Curr Opin Ophthalmol 1997;8:13-8. |
59. | Brιzin AP, Bιchetoille A, Hamard P, Valtot F, Berkani M, Belmouden A, et al. Genetic heterogeneity of primary open angle glaucoma and ocular hypertension: linkage to GLC1A associated with an increased risk of severe glaucomatous optic neuropathy. J Med Genet 1997;34:546-52. |
60. | Stoilova D, Child A, Trifan OC, Crick RP, Coakes RL, Sarfarazi M. Localization of a locus (GLC1B) for adult-onset primary open angle glaucoma to the 2cen-q13 region. Genomics 1996;36:142-50. |
61. | Wirtz MK, Samples JR, Kramer PL, Rust K, Topinka JR, Yount J, et al. Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q. Am J Hum Genet 1997;60:296-304. |
62. | Trifan OC, Traboulsi EI, Stoilova D, Alozie I, Nguyen R, Raja S, et al. A third locus (GLC1D) for adult-onset primary open-angle glaucoma maps to the 8q23 region. Am J Ophthalmol 1998;126:17-28. |
63. | Sarfarazi M, Child A, Stoilova D, Brice G, Desai T, Trifan OC, et al. Localization of the fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to the 10p15-p14 region. Am J Hum Genet 1998;62:641-52. |
64. | Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 2002;295:1077-9. |
65. | Wirtz MK, Samples JR, Rust K, Lie J, Nordling L, Schilling K, et al. GLC1F, a new primary open-angle glaucoma locus, maps to 7q35-q36. Arch Ophthalmol 1999;117:237-41. |
66. | Monemi S, Spaeth G, DaSilva A, Popinchalk S, Ilitchev E, Liebmann J, et al. Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1. Hum Mol Genet 2005;14:725-33. |
67. | Samples JR, Sykes RL, Man J, Rust K, Kramer PL, Wirtz MK. GLC1G: mapping a new POAG locus on chormosome 5. Paper presented at: ARVO Abstract: 4622, Forte Lauderdale; 2004. |
68. | Hewitt AW, Dimasi DP, Mackey DA, Craig JE. A Glaucoma Case-control Study of the WDR36 Gene D658G sequence variant. Am J Ophthalmol 2006;142:324-5. |
69. | Yang J, Patil RV, Yu H, Gordon M, Wax MB. T cell subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am J Ophthalmol 2001;131:421-6. |
70. | Hauser MA, Sena DF, Flor J, Walter J, Auguste J, Larocque-Abramson K, et al. Distribution of optineurin sequence variations in an ethnically diverse population of low-tension glaucoma patients from the United States. J Glaucoma 2006;15:358-63. |
71. | Wang DY, Fan BJ, Canlas O, Tam PO, Ritch R, Lam DS, et al. Absence of myocilin and optineurin mutations in a large Philippine family with juvenile onset primary open angle glaucoma. Mol Vis 2004;10:851-6. |
72. | Duggal P, Klein AP, Lee KE, Iyengar SK, Klein R, Bailey-Wilson JE, et al. A genetic contribution to intraocular pressure: the beaver dam eye study. Invest Ophthalmol Vis Sci 2005;46:555-60. |
73. | Faucher M, Anctil JL, Rodrigue MA, Duchesne A, Bergeron D, Blondeau P, et al. Founder TIGR/myocilin mutations for glaucoma in the Quebec population. Hum Mol Genet 2002;11:2077-90. |
74. | Shimizu S, Lichter PR, Johnson AT, Zhou Z, Higashi M, Gottfredsdottir M, et al. Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma. Am J Ophthalmol 2000;130:165-77. |
75. | Alward WL, Kwon YH, Kawase K, Craig JE, Hayreh SS, Johnson AT, et al. Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma. Am J Ophthalmol 2003;136:904-10. |
76. | Wiggs JL, Auguste J, Allingham RR, Flor JD, Pericak-Vance MA, Rogers K, et al. Lack of association of mutations in optineurin with disease in patients with adult-onset primary open-angle glaucoma. Arch Ophthalmol 2003;121:1181-3. |
77. | Tang S, Toda Y, Kashiwagi K, Mabuchi F, Iijima H, Tsukahara S, et al. The association between Japanese primary open-angle glaucoma and normal tension glaucoma patients and the optineurin gene. Hum Genet 2003;113:276-9. |
78. | Hashizume K, Mashima Y, Fumayama T, Ohtake Y, Kimura I, Yoshida K, et al. Genetic polymorphisms in the angiotensin II receptor gene and their association with open-angle glaucoma in a Japanese population. Invest Ophthalmol Vis Sci 2005;46:1993-2001. |
79. | Ishikawa K, Funayama T, Ohtake Y, Kimura I, Ideta H, Nakamoto K,et al. Association between glaucoma and gene polymorphism of endothelin type A receptor. Mol Vis 2005;11:431-7. |
80. | Vickers JC, Craig JE, Stankovich J, McCormack GH, West AK, Dickinson JL, et al. The apolipoprotein epsilon4 gene is associated with elevated risk of normal tension glaucoma. Mol Vis 2002;8:389-93. |
81. | Aung T, Ocaka L, Ebenezer ND, Morris AG, Brice G, Child AH, et al. Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma. Hum Genet 2002;110:513-4. |
82. | Juronen E, Tasa G, Veromann S, Parts L, Tiidla A, Pulges R, et al. Polymorphic glutathione S-transferase M1 is a risk factor of primary open-angle glaucoma among Estonians. Exp Eye Res. 2000;71:447-52. |
83. | Melki R, Colomb E, Lefort N, Brιzin AP, Garchon HJ. CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma. J Med Genet 2004;41:647-51. |
84. | Melki R, Lefort N, Brιzin AP, Garchon HJ. Association of a common coding polymorphism (N453S) of the cytochrome P450 1B1 (CYP1B1) gene with optic disc cupping and visual field alteration in French patients with primary open-angle glaucoma. Mol Vis 2005;11:1012-7. |
85. | Tsai FJ, Lin HJ, Chen WC, Tsai CH, Tsai SW. A codon 31ser-arg polymorphism of the WAF-1/CIP-1/p21/tumour suppressor gene in Chinese primary open-angle glaucoma. Acta Ophthalmol Scand 2004;82:76-80. |
86. | Funayama T, Ishikawa K, Ohtake Y, Tanino T, Kurosaka D, Kimura I, et al. Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma. Invest Ophthalmol Vis Sci 2004;45:4359-67. |
87. | Fan BJ, Wang DY, Fan DS, Tam PO, Lam DS, Tham CC, et al. SNPs and interaction analyses of myocilin, optineurin, and apolipoprotein E in primary open angle glaucoma patients. Mol Vis 2005;11:625-31. |
88. | Scheie HG, Cameron JD. Pigment dispersion syndrome: a clinical study. Br J Ophthalmol 1981;65:264-9. |
89. | Anderson JS, Parrish R, Greenfield D. A second locus for the pigment dispersion syndrome and pigmentary glaucoma maps to 18qll-q21. Am J Hum Genet 1998;63:A279. |
90. | John SW, Smith RS, Savinova OV, Hawes NL, Chang B, Turnbull D, et al. Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci 1998;39:951-62. |
91. | Anderson MG, Smith RS, Hawes NL, Zabaleta A, Chang B, Wiggs JL,et al. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat Genet 2002;30:81-5. |
92. | Damji KF, Bains HS, Stefansson E, Loftsdottir M, Sverrisson T, Thorgeirsson E, et al. Is pseudoexfoliation syndrome inherited? A review of genetic and nongenetic factors and a new observation. Ophthalmic Genet 1998;19:175-85. |
93. | Bialasiewicz AA, Wali U, Shenoy R, Al-Saeidi R. Patients with secondary open-angle glaucoma in pseudoexfoliation (PEX) syndrome among a population with high prevalence of PEX. Clinical findings and morphological and surgical characteristics. Ophthalmologe 2005;102:1064-8. |
94. | Wiggs JL, Andersen JS, Stefansson E. A genomic screen suggests a locus on chromosome 2p16 for pseudoexfoliation syndrome. Am J Hum Genet 1998;63:A314. |
95. | Stefansson DE, Loftsdottir M, Sverrisson T. Maternal inheritance in pseudoexfoliation syndrome. Am J Hum Genet 1998;63:A324. |
96. | Introduction to glaucoma: Terminology, Epidemiology, and Heridity. In: Liesegang TJ, Skuta GL, Cantor LB, editors. Glaucoma, section 10. San Francisco: American Academy of Ophthalmology; 2004-2005. p. 10. |
[Table 1], [Table 2], [Table 3], [Table 4]
|