REFINING THE LOCUS FOR BEST VITELLIFORM MACULAR DYSTROPHY AND MUTATION ANALYSIS OF THE CANDIDATE GENE ROM-I

Vitelliform macular dystrophy (Best disease) is an autosomal dominant macular dystrophy which shares important clinical features with age-re lated macular degeneration, the most common cause of legal blindness i n the elderly. Unfortunately, our understanding and treatment for this common age-related disorder is limited. Discovery of the gene which c auses Best disease has the potential to increase our understanding of the pathogenesis of all types of macular degeneration, including the c ommon age-related form. Best disease has recently been mapped to chrom osome 11q13. The photoreceptor-specific protein ROM1 has also been rec ently mapped to this location, and the ROM1 gene is a candidate gene f or Best disease. Using highly polymorphic markers, we have narrowed th e genetic region which contains the Best disease gene to the 10-cM reg ion between markers D11S871 and PYGM. Marker D11S956 demonstrated no r ecombinants with Best disease in three large families and resulted in a lod score of 18.2. In addition, a polymorphism within the ROM1 gene also demonstrated no recombinants and resulted in a lod score of 10.0 in these same three families. We used a combination of SSCP analysis, denaturing gradient gel electrophoresis, and DNA sequencing to screen the entire coding region of the ROM1 gene in 11 different unrelated pa tients affected with Best disease. No nucleotide changes were found in the coding sequence of any affected patient, indicating that mutation s within the coding sequence are unlikely to cause Best disease.