Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration

Mutations in ABCR (ABCA4) have been reported to cause a spectrum of autosom al recessively inherited retinopathies, including Stargardt disease (STGD), cone-rod dystrophy and retinitis pigmentosa. Individuals heterozygous for ABCR mutations may be predisposed to develop the multifactorial disorder ag e-related macular degeneration (AMD). We hypothesized that some carriers of STGD alleles have an increased risk to develop AMD. We tested this hypothe sis in a cohort of families that manifest both STGD and AMD. With a direct- sequencing mutation detection strategy, we found that AMD-affected relative s of STGD patients are more likely to be carriers of pathogenic STGD allele s than predicted based on chance alone. We further investigated the role of AMD-associated ABCR mutations by testing for expression and ATP-binding de fects in an in vitro biochemical assay. We found that mutations associated with AMD have a range of assayable defects ranging from no detectable defec t to apparent null alleles. Of the 21 missense ABCR mutations reported in p atients with AMD, 16 (76%) show abnormalities in protein expression, ATP-bi nding or ATPase activity. We infer that carrier relatives of STGD patients are predisposed to develop AMD.