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 ABC7gene 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.

The hydrogenase-like Nar1p is essential for maturation of cytosolic and nuclear iron–sulphur proteins

“…For iron regulation, the organelles seem to use a product of the Fe/S protein metabolism, but not haeme, the other major iron-containing compound synthesised by mitochondria. This behaviour is notably different from human cells, which accumulate iron not only after Fe/S protein biogenesis defects, but also as a result of impaired porphyrin metabolism (Bekri et al, 2000;Cazzola et al, 2003). Despite the less complex regulation of iron uptake and distribution in yeast cells, our current study suggests that, under the assumption of a direct function of Nar1p in maturation of all extramitochondrial Fe/S proteins, a cytosolic or nuclear Fe/S protein is unlikely to be involved in this regulatory circuit.…”

An essential function of the mitochondrial sulfhydryl oxidase Erv1p/ALR in the maturation of cytosolic Fe/S proteins

“…To date, only one component with a specific function in cytosolic Fe/S protein maturation has been identified, the Saccharomyces cerevisiae ABC transporter Atm1p of the mitochondrial inner membrane. The protein is present in all eukaryotes including man (ABC7; Bekri et al, 2000) and plants (Sta1; Kushnir et al, 2001), and has been proposed to export from the mitochondrial matrix a component required for assembly of Fe/S proteins in the cytosol.…”

Pathophysiology and genetic mutations in congenital sideroblastic anemia

“…XLSA/A patients present with mild anemia and elevated red blood cell protoporphyrin IX (PPIX), with motor delay and evidence of spinocerebellar dysfunction, including early onset ataxia associated with severe cerebellar hypoplasia. 21,22 Systemic iron overload has not been reported in this disease. From the results of molecular analysis, XLSA/A is due to mutations in the adenosine triphosphate (ATP) binding cassette B7 (ABCB7) gene, which is located at Xp13.3 and encodes an essential component of the [Fe-S] cluster machinery.…”