A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family

PURPOSE. To describe a novel gene causing a Stargardt-like phenotype in a f amily with dominant macular dystrophy and the exclusion of all known genes within the disease locus. METHODS. Meiotic breakpoint mapping in a family of 2314 individuals enabled refinement of the location of the disease gene. The genomic organization a nd expression profile of known and putative genes within the critical regio n were determined using bioinformatics, cDNA cloning, and RT-PCR. The codin g sequence of genes expressed within the retina was scanned for mutations, by using DNA sequencing. RESULTS. The disease-causing gene (STGD3) was further localized to 562 kb o n chromosome 6 between D6S460 and a new polymorphic marker centromeric to D 6S1707. Of the four genes identified within this region, all were expressed in the retina or retinal pigment epithelium. The only coding DNA sequence variant identified in these four genes was a 5-bp deletion in exon 6 of ELO VL4. The deletion is predicted to lead to a truncated protein with a net lo ss of 44 amino acids, including a dilysine endoplasmic reticulum. retention motif. The ELOVL4 gene is the fourth known example of a predicted human pr otein with homology to mammalian. and yeast enzymes involved in the membran e-bound fatty acid chain elongation system. The genomic organization of ELO VL4 and primer sets for exon amplification are presented. CONCLUSIONS. ELOVL4 causes macular dystrophy in this large family distribut ed throughout North America and implicates fatty acid biosynthesis in the p athogenesis of macular degeneration. The PCR-based assay for the 5-bp delet ion will facilitate more accurate genetic counseling and identification of other branches of the family.