Evidence for Digenic Inheritance in Adult–onset Primary Open Angle Glaucoma.

Abstract

Abstract: : Purpose: Primary open angle glaucoma (POAG) is known to be a complex disease. Potentially more than one POAG gene may be segregating through families with glaucoma. Therefore, we determined if myocilin mutations are present in our GLC1C families. Methods: DNA from 73 members of the Greek GLC1C family, 65 members of the US GLC1C family and 56 random POAG patients from Greece was used for myocilin exon 3 analysis. WAVEMAKER software (Transgenomic, Omaha, NE) was used to design four amplicons encompassing exon 3 of myocilin that would be optimal for identifying heteroduplex DNA. The resultant PCR products were then analyzed using the Transgenomic WAVE^TM dHPLC system. Results:Screening of the Greek GLC1C family for myocilin variants identified the T377M mutation in 19 out of 73 family members. No myocilin mutations were found in the Oregon GLC1C family. While all POAG individuals from the Greek family had the GLC1C disease haplotype, only 8 of them also had the T377M MYOC mutation. Penetrance of POAG in individuals over the age of 40 was higher (89% vs 50%) in those individuals possessing both the T377M MYOC and GLC1C haplotype compared to individuals carrying only one POAG gene. Two polymorphisms but no myocilin mutations including the T377M were identified in 56 random POAG individuals from the Epirus region of Greece. Preliminary evidence suggests that the Australian POAG families with the T377M may share the GLC1A disease haplotype with our Greek GLC1C family. Further work is in process to determine if the T377M results from a founder effect. Conclusions:This is the first report of potential digenic inheritance of POAG genes in the more common late–onset form of high pressure primary open angle glaucoma. The incidence of myocilin mutations in the Greek POAG population appears to be lower than 3%.

Keywords: genetics • clinical (human) or epidemiologic studies: risk factor assessment • mutations