Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation

The human protein ABC7 belongs to the adenosine triphosphate-binding casset te transporter superfamily, and its yeast orthologue, Atm1p, plays a centra l 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 sideroblast ic anemia with cerebellar ataxia (XLSA/A), Here, the promoter region and th e intron/axon 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 f ollowing 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 cha rge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7, Express ion of normal ABC7 almost fully complemented the defect in the maturation o f cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Delta atm1 cells). Thus, ABC7 is a functional orthologue of Atm1p , In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) prot eins In Delta 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 ABC 7 mutation in the reported family. (C) 2000 by The American Society of Hema tology.