title: Biochemical defects in ABCR protein variants associated with human retinopathies.
abstract: Mutations in the gene encoding ABCR (ABCA4), a photoreceptor-specific ATP-binding cassette (ABC) transporter, are responsible for autosomal recessive Stargardt disease (STGD), an early onset macular degeneration, and some forms of autosomal recessive cone-rod dystrophy and autosomal recessive retinitis pigmentosa. Heterozygosity for ABCA4 mutations may also represent a risk factor for age-related macular degeneration (AMD), although this idea is controversial. An ongoing challenge in the analysis of ABCA4-based retinopathies arises from the observation that most of the ABCA4 sequence variants identified so far are missense mutations that are rare in both patient and control populations. With the current sample size of most sequence variants, one cannot determine statistically whether a particular sequence variant is pathogenic or neutral. A related challenge is to determine the degree to which each pathogenic variant impairs ABCR function, as genotype-phenotype analyses indicate that age of onset and disease severity correlate with different ABCA4 alleles. To address these questions, we performed a functional analysis of human ABCR and its variants. These experiments reveal a wide spectrum of biochemical defects in these variants and provide insight into the transport mechanism of ABCR.
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.forename: P M
authors.initials: PM
authors.lastname: Smallwood
authors.forename: J
authors.initials: J
authors.lastname: Nathans
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D005128:Eye Diseases / Q000235:genetics*; D005808:Genes, Recessive; D014644:Genetic Variation; D006801:Humans; D007700:Kinetics; D008268:Macular Degeneration / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics; D012374:Rod Cell Outer Segment / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate