Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A)

X-linked sideroblastic anemia and ataxia (XLSA/A) is a recessive disorder c haracterized by an infantile to early childhood onset of non-progressive ce rebellar ataxia and mild anemia with hypochromia and microcytosis. A gene e ncoding an ATP-binding cassette (ABC) transporter was mapped to Xq13, a reg ion previously shown by linkage analysis to harbor the XLSA/A gene. This ge ne, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis. The f ull-length ABC7 cDNA was cloned and the entire coding region screened for m utations in a kindred in which five male members manifested XLSA/A. An I400 M variant was identified in a predicted transmembrane segment of the ABC7 g ene in patients with XLSA/A. The mutation was shown to segregate with the d isease in the family and was not detected in at least 600 chromosomes of ge neral population controls. Introduction of the corresponding mutation into the Saccharomyces cerevisiae ATM1 gene resulted in a partial loss of functi on of the yeast Atm1 protein. In addition, the human wild-type ABC7 protein was able to complement ATM1 deletion in yeast. These data indicate that AB C7 is the causal gene of XLSA/A and that XLSA/A is a mitochondrial disease caused by a mutation in the nuclear genome.