Molecular genetic studies of primary open angle and angle closure glaucoma
Glaucoma, a group of heterogeneous optic neuropathies characterized by progressive visual field loss, is the leading cause of irreversible blindness worldwide. The condition has a substantial heritable basis, as illustrated by the numerous loci and genes identified to date, and the large proportion of patients having a family history. Categorized according to the anatomy of the anterior chamber angle, there are 2 main forms of glaucoma, primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG). The first half of the thesis describes the molecular genetic study of POAG, while the latter deals with PACG. Primary open angle glaucoma (POAG) accounts for most glaucoma in Caucasian and Afro-Caribbean populations. The condition is classified according to the presence of elevated intraocular pressure (IOP) into high- tension glaucoma (HTG) or normal tension glaucoma (NTG). OPAl, the gene responsible for autosomal dominant optic atrophy represents an excellent candidate gene for POAG (in particular NTG). Single nucleotide polymorphisms on intervening sequence (IVS) 8 of the 0/M7gene (genotype IVS 8 +4 C/T; +32 T/C) were found to be strongly associated with a fifth of NTG cases and may be a marker for disease association, providing the first evidence of an association between OPAl and NTG. However this OPAl genotype was not found to be significantly associated with HTG. Further work did not detect a significant difference in a range of phenotypic features in NTG patients with and without these OPAl polymorphisms, suggesting that these specific genetic variations do not underlie any major phenotypic diversity in NTG. Optineurin (OPTTN), in the GLC1E interval on chromosome 10p, was recently identified as the second gene underlying POAG, with a common mutation, E50K, being found in 13.5% of families, and a M98K variant identified as a significant risk-associated genetic factor for POAG. However when a large panel of 315 sporadic adult POAG subjects were examined for these 2 OPTN sequence variants, the E50K mutation was identified in only 1.5% of NTG subjects, making it an infrequent cause of sporadic NTG. The M98K variant was found to be associated specifically with NTG but not HTG, suggesting allelic heterogeneity between these 2 phenotypes. A characteristic NTG phenotype comprising a young-adult age of onset, advanced visual loss and progressive disease, has been described in individuals carrying the E50K OPTN mutation. Primary angle closure glaucoma (PACG) is the main form of glaucoma in East Asian populations. Two large Singaporean PACG families were examined and the first locus for the disease was identified on chromosome 10 using linkage analysis. The disease interval was refined to 5.0 cM on chromosome 10qll flanked by the markers D10S225 and D10S568, with the maximum LOD score of 3.4 at 0=.00 for D10S220. Several genes, GDF10, TIM23, SLC18A3 and ASAH2 were excluded as candidates for this condition. This molecular genetic study of both POAG and PACG has contributed to our knowledge of glaucoma.