title: Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation.
abstract: The human protein ABC7 belongs to the adenosine triphosphate-binding cassette transporter superfamily, and its yeast orthologue, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe/S) cluster-containing proteins. Previously, a missense mutation in the human ABC7 gene was shown to be the defect in members of a family affected with X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). Here, the promoter region and the intron/exon structure of the human ABC7 gene were characterized, and the function of wild-type and mutant ABC7 in cytosolic Fe/S protein maturation was analyzed. The gene contains 16 exons, all with intron/exon boundaries following the AG/GT rule. A single missense mutation was found in exon 10 of the ABC7 gene in 2 affected brothers with XLSA/A. The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7. Expression of normal ABC7 almost fully complemented the defect in the maturation of cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Deltaatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Deltaatm1 cells led to a low efficiency of cytosolic Fe/S protein maturation. These data demonstrate that both the molecular defect in XLSA/A and the impaired maturation of a cytosolic Fe/S protein result from an ABC7 mutation in the reported family.
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bekri
authors.forename: G
authors.initials: G
authors.lastname: Kispal
authors.forename: H
authors.initials: H
authors.lastname: Lange
authors.forename: E
authors.initials: E
authors.lastname: Fitzsimons
authors.forename: J
authors.initials: J
authors.lastname: Tolmie
authors.forename: R
authors.initials: R
authors.lastname: Lill
authors.forename: D F
authors.initials: DF
authors.lastname: Bishop
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D000756:Anemia, Sideroblastic / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000503:physiopathology; D003001:Cloning, Molecular; D017931:DNA Primers; D005091:Exons; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009679:Nuclear Family; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012441:Saccharomyces cerevisiae; D014960:X Chromosome
chemical_list: C113037:ABCB7 protein, human; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers