title: Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A).
abstract: X-linked sideroblastic anemia and ataxia (XLSA/A) is a recessive disorder characterized by an infantile to early childhood onset of non-progressive 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 an ortholog of the yeast ATM1 gene 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 gene 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 Saccharomyces cerevisiae ATM1 gene resulted in a partial loss of function 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 ABC7 is the causal gene of XLSA/A and that XLSA/A is a mitochondrial disease caused by a mutation in the nuclear genome.
authors: Intramural Research Support Program, SAIC-Frederick and Laboratory of Genomic Diversity, National Cancer Institute, Building 560, Room 21-18, Frederick Cancer Research and Development Center, Frederick, MD 21702-1201, USA.
authors: R
authors: R
authors: Allikmets
authors: W H
authors: WH
authors: Raskind
authors: A
authors: A
authors: Hutchinson
authors: N D
authors: ND
authors: Schueck
authors: M
authors: M
authors: Dean
authors: D M
authors: DM
authors: Koeller
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000756:Anemia, Sideroblastic / Q000235:genetics*; D015152:Blotting, Northern; D002524:Cerebellar Ataxia / Q000235:genetics*; D003001:Cloning, Molecular; D005260:Female; D005296:Ferrous Compounds / Q000494:pharmacology; D005656:Fungal Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D014960:X Chromosome
chemical_list: C113037:ABCB7 protein, human; C091561:ATM1 protein, S cerevisiae; D018528:ATP-Binding Cassette Transporters; D005296:Ferrous Compounds; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D007501:Iron; C029451:ferrous chloride