Abstract 788 Genetic Basis of Disease I Platform, Monday, 5/3

X-linked sideroblastic anemia and ataxia (XLSA/A) is a recessive disorder characterized by an infantile to early childhood onset of nonprogressive cerebellar ataxia and mild anemia with hypochromia and microcytosis. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to Xq13, a region previously shown by linkage analysis to harbor the XLSA/A gene. This gene, ABC7, is capable of complementing a yeast ABC transporter, ATM1, whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis. The full-length ABC7 cDNA was cloned and the entire coding region screened for mutations in a kindred in which five male members manifested XLSA/A. An I400M variant was identified in a predicted transmembrane segment of the ABC7 protein in patients with XLSA/A. The mutation was shown to segregate with the disease in the family and was not detected in at least 600 chromosomes of general population controls. Introduction of the corresponding mutation into the S. cerevisiae ATM1 gene resulted in a partial loss of function of the yeast ATM1 protein. These data indicate that ABC7 is the causal gene of XLSA/A and that XLSA/A is a mitochondrial disease due to a mutation in the nuclear genome.