Genetic homogeneity for inherited congenital microcoria loci inan Asian Indian pedigree

摘要

Purpose: Congenital microcoria is a rare autosomal dominantdevelopmental disorder of the iris associated with myopia and juvenileopen angle glaucoma. Linkage to the chromosomal locus 13q31-q32 haspreviously been reported in a large French family. In the current study,a three generation Asian Indian family with 15 congenital microcoria(pupils with a diameter 2 mm) affected members was studied forlinkage to candidate microsatellite markers at the 13q31-q32 locus.Methods: Twenty-four members of the family were clinically examinedand genomic DNA was extracted. Microsatellite markers at 13q31-q32 werePCR amplified and run on an ABI Prism 310 genetic analyzer and genotypedwith the GeneScan analysis. Two point and multipoint linkage analyseswere performed using the MLINK and SUPERLINK programs.Results: Peak two point LOD scores of 3.5, 4.7, and 5.3 were foundco-incident with consecutive markers D13S154, DCT, and D13S1280.Multipoint analysis revealed a 4 cM region encompassing D13S1300 toD13S1280 where the LOD remains just over 6.0 Thus we confirmlocalization of the congenital microcoria locus to chromosomal locus13q31-q32. In addition, eight individuals who had both microcoria andglaucoma were screened for glaucoma genes: myocilin (MYOC),optineurin (OPTN) and CYP1B1. Using direct sequencing a pointmutation (144 GA) resulting in a Q48H substitution in exon 1 of theMYOC gene was observed in five of the eight glaucoma patients, butnot in unaffected family members and 100 unrelated controls.Conclusions: We have confirmed the localization of the congenitalmicrocoria locus (MCOR) to 13q31-q32 in a large Asian Indian family andconclude that current information suggests this is a single locusdisorder and genetically homogeneous. When combined with the initiallinkage paper our haplotype and linkage data map the MCOR locus to a 6-7cM region between D13S265 and D13S1280. The DCT locus, a member of thetyrosinase family involved in pigmentation, maps within this region.Data presented here supports the hypothesis that congenital microcoriais a potential risk factor for glaucoma, although this observation iscomplicated by the partial segregation of MYOC Q48H (1q24.3-q25.2), amutation known to be associated with glaucoma in India. Fine mapping andcandidate gene analysis continues with the hope that characterizing themicocoria gene will lead to a better understanding of microcoria andglaucoma causation. The relationship between microcoria, glaucoma, andthe MYOC Q48H mutation in this family is discussed.