Novel causative gene identified for adult-onset POAG

"Glaucoma is a leading cause of blindness in virtually every country, with about 67 million individuals affected worldwide. Glaucoma is usually an asymptomatic disease until the late stages when irreversible damage has already occurred. [POAG] is the most prevalent form of the disease. However, to date only two genes have been identified in association with POAG. Because of this, there is an urgent need to diagnose glaucoma during the early stages and to begin appropriate neuroprotective treatment when damage can be prevented," according to the authors of the study, who spoke at the Association for Research in Vision and Ophthalmology annual meeting.

Dr. Monemi et al. initially studied two large families with POAG. The first family (POAG-527) in which glaucoma was linked to the GLCIG locus had 108 members in four generations and of these 54 individuals took part in the study; seven family members were affected, five had suspected glaucoma, and 42 were unaffected. The second family (POAG-002) had glaucoma that was not linked to the GLCIG locus and had 99 family members in five generations, 40 of whom participated in the study. Of these, 13 members were affected, four had ocular hypertension, and 23 were unaffected. Thirty-two individuals from the two families were used for the genome scan.

In a separate study by the same laboratory, another 638 persons (139 families) that included more than 400 glaucoma subjects were screened for the entire genome. Because of this work, seven families with linkage to the region of 5q were identified. The Human Nomenclature Committee has designed the newly identified POAG locus as GLCIG. This and work done by another group of investigators defined the GLC1G locus between D5S1466 and D5S180 and reduced the critical region of interest further to 2 megabases.

"This critical region of the GLC1G locus contained seven known genes (MAN2A1, AK125070, BC017169, TSLP, WDR36, CAMK4, and STARD4) and at least three other predicted genes. Analysis of genomic DNA from at least two affected subjects of the original GLC1G-linked family of POAG-527 revealed four sequence alterations in only two genes. Three of these variations were polymorphisms and only one sequence change in the WDR36 gene proved to be significant," the authors reported in Human Molecular Genetics (2005;14:725-733).

The initial sequence variation identified in the WDR36 gene (D658G) was present in all seven affected members of the first family linked to the GLC1G locus, but this alteration was not found in almost 500 normal control chromosomes. Further screening of this gene in 130 families identified 24 DNA alterations, four of which (D658G, N355S, A449T, and R529Q) were considered as glaucoma-causing mutations. These mutations were found in 17 patients with POAG who were not related to each other. These mutations were not found in at least 200 normal chromosomes.