North Carolina macular dystrophy (MCDR1) locus: A fine resolution genetic map and haplotype analysis

Purpose: We previously reported linkage of North Carolina macular dystrophy in a single isolated family to a broad region on chromosome 6q16. In order to refine the localization of the MCDR1 gene (North Carolina macular dystr ophy), additional families with this disease and new markers were studied. Methods: We ascertained 10 families with the North Carolina macular dystrop hy phenotype (MCDR1). These families were of various ethnic and geographic origins such as Caucasian, Mayan Indian, African-American, French, British, German, and American of European decent. Two hundred thirty-two individual s in these families underwent comprehensive ophthalmic examinations and blo od was collected for genotyping. One hundred seventeen were found to be aff ected. Linkage simulation studies were performed. Two-point linkage, haplot ype analysis, and multipoint linkage was performed using VITESSE and FASTLI NK. HOMOG was used to test for genetic heterogeneity. Results: The clinical features were consistent with the diagnosis of North Carolina macular dystrophy in all families. Multipoint linkage analysis ind icates that the MCDR1 gene is in the interval between D6D249 and D6S1671 wi th a maximum LOD score of 41.52. There was no evidence of genetic heterogen eity among the families studied. Families 765, 768, 772, 1193, and 1292 sha red the same chromosomal haplotype in this region. Conclusions: This is the largest single data set of families with the MCDR1 phenotype. The single large family from North Carolina continues to be inf ormative for the closest flanking markers and alone supports the minimal ca ndidate region as suggested by previous studies. There remains no evidence of genetic heterogeneity in this disease. Most of the American families app ear to have descended from the same ancestral mutation. The remaining famil ies could each represent independent origins of the mutation in the MCDR1 g ene.