title: Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration.
abstract: Mutations in ABCR (ABCA4) have been reported to cause a spectrum of autosomal 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 age-related macular degeneration (AMD). We hypothesized that some carriers of STGD alleles have an increased risk to develop AMD. We tested this hypothesis in a cohort of families that manifest both STGD and AMD. With a direct-sequencing mutation detection strategy, we found that AMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. We further investigated the role of AMD-associated ABCR mutations by testing for expression and ATP-binding defects in an in vitro biochemical assay. We found that mutations associated with AMD have a range of assayable defects ranging from no detectable defect to apparent null alleles. Of the 21 missense ABCR mutations reported in patients with AMD, 16 (76%) show abnormalities in protein expression, ATP-binding or ATPase activity. We infer that carrier relatives of STGD patients are predisposed to develop AMD.
authors.affiliation: Program in Cell and Molecular Biology, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Shroyer
authors.forename: R A
authors.initials: RA
authors.lastname: Lewis
authors.forename: A N
authors.initials: AN
authors.lastname: Yatsenko
authors.forename: T G
authors.initials: TG
authors.lastname: Wensel
authors.forename: J R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000483:Alleles; D015153:Blotting, Western; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016296:Mutagenesis; D009154:Mutation; D010375:Pedigree; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D014162:Transfection
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D008565:Membrane Proteins; D000255:Adenosine Triphosphate; D004247:DNA