Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1

Abstract

Glaucoma is a leading cause of blindness in virtually every country. Development of an accurate diagnostic test for presymptomatic detection of individuals at risk is an urgent requisition for this condition. Herein, we report mapping of a new adult-onset primary open-angle glaucoma (POAG) locus on 5q22.1 (GLC1G) and identification of its defective gene. Mutation screening of seven candidate genes from the GLC1G critical region (approximately 2 Mb between D5S1466 and D5S2051) identified only one significant alteration in the WDR36 (WD40-repeat 36) gene. This mutation (i.e. D658G) was segregated in all affected members of our first GLC1G-linked family but it was absent in 476 normal control chromosomes. Further screening of WDR36 in a total of 130 POAG families revealed 24 DNA variations. Overall, four mutations (N355S, A449T, R529Q and D658G) were identified in 17 (5.02-6.92%) unrelated POAG subjects, 11 with high-pressure and six with low-pressure glaucoma. These mutations were absent in a minimum of 200 normal control chromosomes and, further they were conserved between WDR36 orthologues in mouse, rat, dog, chimp and human. WDR36 is a novel gene with 23 exons, which encodes for 951 amino acids and a protein with multiple G-beta WD40 repeats. By northern blotting, two distinct mRNA transcripts of 5.9 and 2.5 kb were observed in human heart, placenta, liver, skeletal muscle, kidney and pancreas. WDR36 gene expression in lens, iris, sclera, ciliary muscles, ciliary body, trabecular meshwork, retina and optic nerve were established by RT-PCR. In mouse, two transcripts of 3.5 and 2.9 kb showed analogous expression patterns to human. mRNA expressions were detected in 7-, 11-, 15- and 17-day-old developing mouse embryos. In summary, WDR36 is a novel causative gene for adult-onset POAG at the GLC1G locus. Specific ocular expressions and observed mutations are consistent with WDR36 role in etiology of both high- and low-pressure glaucoma.

The genetic mechanisms of primary angle closure glaucoma

“…55,56 Moreover, it has been shown that the size of the anterior chamber is strongly determined by genetic components, suggesting that morphological characteristics predisposing to PACG are also heritable. 52,53 Recent advances have indicated several genes and genetic loci [57][58][59][60] that may be causative for POAG, but evidence for genes causing PACG remains sparse. The first evidence for a genetic locus linked to familial PACG comes from the analysis of a large family with nanophthalmos, hyperopia, and angle closure glaucoma.…”

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

“…Only three genes causing POAG, MYOC, optineurin (OPTN), and WDR36, have been identified in these loci, that is, in GLC1A, GLC1E, and GLC1G, respectively. 9,13,46 Rare mutations associated with POAG in a novel gene, neurotrophin-4 (NTF4), have been recently identified in a European, as well as in a Chinese population. 47,48 A review of the literature on glaucoma genetics suggests a useful separation of them into those which are well-established glaucoma-causing genes, controversial genes that do not have an established role in glaucoma pathogenicity at present, and low-penetrance risk alleles that contribute to the likelihood of getting disease, but don't cause disease on their own.…”

“…Monemi et al 46 observed that one of the four identified disease-causing mutations of WDR36, D658G, maps to the C-terminal part of the cytochrome heme cd1 domain, which is part of an enzyme with cytochrome oxidase activity. A gene responsible for primary congenital glaucoma, cytochrome P450, subfamily 1, polypeptide 1 (CYP1B1), is also a member of the cytochrome P450 family.…”

Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma

“…7 However, only three causative genes have been described so far, including: myocilin (MYOC/GLC1A), 8 optineurin (OPTN/GLC1E) 9 and WD repeat domain 36 (WDR36/GLC1G). 10 Altogether, mutations in these genes account for o10% of POAG cases. 11 In addition, association studies have implicated at least 20 other genes, 7,12 among them cytochrome P450-1B (CYP1B1) 13 and neurotrophin 4 (NTF4), 14 contributing to the pathogenesis of glaucoma, 7 but these are still insufficient to explain the most significant fraction of POAG cases.…”