Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia (XLSA/A) with disruption of cytosolic iron–sulfur protein maturation

Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Blood (Impact Factor: 10.45). 12/2000; 96(9):3256-64.
Source: PubMed


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.

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Available from: David F. Bishop, Jun 02, 2014
    • "A bacterial homologue of Atm1 associates with GSH (or GSH derivatives) in a similar location (Lee et al., 2014), suggesting that this interaction is specific and that this region of Atm1 family members may allow the binding of a GSH-containing substrate . One of the GSH-binding residues (yeast D398) corresponds to human E433 that is changed to lysine in patients with X-linked sideroblastic anemia and cerebellar ataxia (XLSA/A) (Bekri et al., 2000). Both yeast Atm1 and human ABCB7 proteins carrying this mutation show diminished activity in the maturation of cytosolic Fe/S proteins. "
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    • "In muscle biopsies, iron labeling (Perl's staining) showed accumulation of iron within mitochondria (Mochel et al., 2008; Kollberg et al., 2009). Mutations in ABCB7 are associated with X-linked sideroblastic anemia with ataxia, a condition that is characterized by the presence of iron-rich perinuclear mitochondria within erythroblasts (sideroblasts) (Allikmets et al., 1999; Bekri et al., 2000). Similarly, a mutation in GLRX5, a protein linked to Fe-S cluster biogenesis, although its function is still unclear (Rodriguez-Manzaneque et al., 2002), was identified in a patient presenting sideroblastic anemia (Camaschella et al., 2007). "
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