Blood, 1 November 2000, Vol. 96, No. 9, pp. 3256-3264
RED CELLS
Human ABC7 transporter: gene structure and mutation causing
X-linked sideroblastic anemia with ataxia with disruption of
cytosolic iron-sulfur protein maturation
Soumeya Bekri,
Gyula Kispal,
Heike Lange,
Edward Fitzsimons,
John Tolmie,
Roland Lill, and
David F. Bishop
From the Department of Human Genetics, Mount Sinai
School of Medicine, New York, NY; the Institut für Zytobiologie
der Philipps-Universität Marburg, Marburg, Germany; and the
Department of Haematology, Western Infirmary and the Duncan Guthrie
Institute of Medical Genetics, Yorkhill, Glasgow, UK.
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 (
atm1 cells). Thus, ABC7
is a functional orthologue of Atm1p. In contrast, the expression of
mutated ABC7 (E433K) or Atm1p (D398K) proteins in atm1 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.
