title: The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease.
abstract: In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype.
authors: Department of Human Genetics, University Hospital Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. A.Maugeri@ANTRG.AZN.NL
authors: A
authors: A
authors: Maugeri
authors: M A
authors: MA
authors: van Driel
authors: D J
authors: DJ
authors: van de Pol
authors: B J
authors: BJ
authors: Klevering
authors: F J
authors: FJ
authors: van Haren
authors: N
authors: N
authors: Tijmes
authors: A A
authors: AA
authors: Bergen
authors: K
authors: K
authors: Rohrschneider
authors: A
authors: A
authors: Blankenagel
authors: A J
authors: AJ
authors: Pinckers
authors: N
authors: N
authors: Dahl
authors: H G
authors: HG
authors: Brunner
authors: A F
authors: AF
authors: Deutman
authors: C B
authors: CB
authors: Hoyng
authors: F P
authors: FP
authors: Cremers
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D003317:Corneal Dystrophies, Hereditary / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005060:Europe / Q000453:epidemiology; D005091:Exons / Q000235:genetics; D018703:Founder Effect; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D015994:Incidence; D015810:Linkage Disequilibrium / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000453:epidemiology / Q000235:genetics
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger