R. Allikmets et al., Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A), HUM MOL GEN, 8(5), 1999, pp. 743-749
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.