Human ABC7 transporter

Gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation

S. Bekri, G. Kispal, H. Lange, E. Fitzsimons, J. Tolmie, R. Lill, D. F. Bishop

Research output: Contribution to journalArticle

202 Citations (Scopus)

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 (Δatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Δatm1 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. (C) 2000 by The American Society of Hematology.

Original languageEnglish
Pages (from-to)3256-3264
Number of pages9
JournalBlood
Volume96
Issue number9
Publication statusPublished - Nov 1 2000

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Iron-Sulfur Proteins
Protein S
Genes
Exons
Mutation
Missense Mutation
Yeast
Introns
Defects
Yeasts
Cerebellar Ataxia
Proteins
Sulfur
Genetic Promoter Regions
Lysine
Siblings
Glutamic Acid
Substitution reactions
Nucleotides
Iron

ASJC Scopus subject areas

  • Hematology

Cite this

Human ABC7 transporter : Gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. / Bekri, S.; Kispal, G.; Lange, H.; Fitzsimons, E.; Tolmie, J.; Lill, R.; Bishop, D. F.

In: Blood, Vol. 96, No. 9, 01.11.2000, p. 3256-3264.

Research output: Contribution to journalArticle

Bekri, S. ; Kispal, G. ; Lange, H. ; Fitzsimons, E. ; Tolmie, J. ; Lill, R. ; Bishop, D. F. / Human ABC7 transporter : Gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. In: Blood. 2000 ; Vol. 96, No. 9. pp. 3256-3264.
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