Linkage Analysis and Molecular Genetic Study of Inherited Congenital Microcoria in an Indian Pedigree – Refining the MCOR Locus At 13q31–q32

Abstract

Purpose: : A three generation Asian Indian family with autosomal dominant congenital microcoria, in which five out of eight members had glaucoma, was previously linked by us to a 7 cM block at 13q31–q32 region. Additional microsatellite markers were used for further refining the MCOR locus. Microcoria and glaucoma in the pedigree did not co–segregate and this was investigated.

Methods: : After clinical examination and informed consent, blood samples were collected from twenty–four members of the family for genomic DNA. Microsatellite marker genotyping was done on ABI Prism 3100 AVANT genetic analyzer. Two point and multipoint linkage analyses were performed by MLINK and SUPERLINK. DCT gene an ideal candidate in this region is being screened.

Results: : Compared to previous studies, the number of individuals with microcoria and glaucoma was higher. Multipoint linkage analysis done earlier revealed a 4 cM non–recombining block encompassing D13S1300 to D13S1280, a probable MCOR gene locus. Additional microsatellite markers in the region revealed a disease segregating haplotype 6–3–5–2–3–1–1–1. Moreover, a point mutation resulting in a Q48H substitution in exon 1 of the MYOC gene was observed in five with glaucoma, but not in unaffected family members or 100 unrelated controls.

Conclusions: : With additional microsatellite markers the linkage of congenital microcoria locus (MCOR) was further refined at 13q31–q32. Data analysis taking notice of MYOC Q48H mutation supports the hypothesis that congenital microcoria is a potential risk factor for glaucoma. By chance introduction of MYOC mutation in two brances of the pedigree could have influenced the manifestation and eventually increased the number of glaucoma patients than expected.

Keywords: genetics • linkage analysis • mutations