Linkage of a Large Pattern Dystrophy Pedigree to Chromosome 6p21

Abstract

Abstract: : Purpose: To map the gene causing pattern dystrophy in a large pedigree with linkage analysis and to evaluate candidate genes within the linkage interval. Methods: Of 38 family members examined, 15 were found to have an abnormal retinal exam. The retinal findings in this family were variable, ranging from subtle RPE changes to atrophy of the central macula, but as a whole were most consistent with a diagnosis of pattern dystrophy. DNA was prepared from the blood of study subjects and typed with genetic markers distributed evenly across the genome. The genotypes were evaluated using the LINKAGE statistics package. The coding sequences of three candidate genes in the linked region (RDS, GCAP1, and GCAP2) were screened for mutations in the proband of the pedigree using both direct DNA sequencing and SSCP analysis. Results: Significant linkage was obtained with several markers on chromosome 6p21 (D6S271 Zmax = 5.4 at theta = 0). Recombinations at markers D6S1650 and D6S1552 defined a linked interval that included genes RDS, GCAP1, and GCAP2. Direct sequencing of these candidate genes revealed no likely disease-causing mutations. Conclusions: The gene causing the pattern dystrophy in this pedigree is located on chromosome 6p21. No mutations were detected in the RDS, GCAP1 and GCAP2 genes. The retinal degeneration in this family may still be due to a mutation in one of these genes, which is not detectable by PCR-based sequencing (e.g. a deletion or a rearrangement). Alternatively, there may be another retinal degeneration gene in close proximity to RDS, GCAP1 and GCAP2.

Keywords: linkage analysis • retinal degenerations: hereditary • genetics