title: ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies.
abstract: ABCA4, also called ABCR, is a retinal-specific member of the ATP-binding cassette (ABC) family that functions in photoreceptor outer segments as a flipase of all-trans retinal. Homozygous and compound heterozygous ABCA4 mutations are associated with various autosomal recessive retinal dystrophies, whereas heterozygous ABCA4 mutations have been associated with dominant susceptibility to age-related macular degeneration in both humans and mice. We analyzed a cohort of 29 arRP families for the mutations in ABCA4 with a commercial microarray, ABCR-400 in addition to direct sequencing and segregation analysis, and identified both mutant alleles in two families (7%): compound heterozygosity for missense (R602W) and nonsense (R408X) alleles and homozygosity for a complex [L541P; A1038V] allele. The missense mutations were analyzed functionally in the photoreceptors of Xenopus laevis tadpoles, which revealed mislocalization of ABCA4 protein. These mutations cause retention of ABCA4 in the photoreceptor inner segment, likely by impairing correct folding, resulting in the total absence of physiologic protein function. Patients with different retinal dystrophies harboring two misfolding alleles exhibit early age-of-onset (AO) (5-12 years) of retinal disease. Our data suggest that a class of ABCA4 mutants may be an important determinant of the AO of disease.
authors.affiliation: Department of Molecular and Human Genetics, Baylor college of Medicine, Houston, TX 77030, USA. jlupski@bcm.tmc.edu
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.forename: Charles M
authors.initials: CM
authors.lastname: Zaremba
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Yatsenko
authors.forename: Milan
authors.initials: M
authors.lastname: Jamrich
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Wensel
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D017510:Protein Folding; D017948:Retinal Rod Photoreceptor Cells / Q000737:chemistry*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases