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Human Molecular Genetics, 2000, Vol. 9, No. 5 795-801
© 2000 Oxford University Press

Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency

Michaela Jaksch1,2, Isla Ogilvie3, Jianbo Yao3, Gisela Kortenhaus4, Hans-Georg Bresser5, Klaus-Dieter Gerbitz1,2 and Eric A. Shoubridge3,+

1Institute of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics and 2Institute of Diabetes Research of the Academic Hospital Schwabing, Koelner Platz 1, 80804 Munich, Germany, 3Montreal Neurological Institute and Department of Human Genetics, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4, 4Gilead Pediatric Centre, Academic Hospital Bielefeld, 33545 Bielefeld, Germany and 5Department of Pediatrics, Klinikum Sued Nuernberg, 90340 Nuernberg, Germany

Mutations in SCO2, a cytochrome c oxidase (COX) assembly gene located on chromosome 22, have recently been reported in patients with fatal infantile cardio­encephalomyopathy and severe COX deficiency in heart and skeletal muscle. The Sco2 protein is thought to function as a copper chaperone. To investigate the extent to which mutations in SCO2 are responsible for this phenotype, a complete sequence analysis of the gene was performed on ten patients in nine families. Mutations in SCO2 were found in three patients in two unrelated families. We detected two missense mutations, one of which (G1541A) results in an E140K substitution adjacent to the highly conserved CxxxC metal-binding site. The other (C1634T) results in an R171W substitution more distant from the copper-binding site. A nonsense codon was found on one allele in two siblings presenting with a rapidly progressive fatal cardio­encephalomyopathy. Interestingly, all patients so far reported are compound heterozygotes for the G1541A mutation, suggesting that this is either an ancient allele or a mutational hotspot. The COX deficiency in patient fibroblasts (~50%) did not result in a measurable decrease in the steady-state levels of COX complex polypeptide subunits and could be rescued by trans­ferring chromosome 22, but not other chromosomes. These data indicate that mutations in SCO2 cause a fatal infantile mitochondrial disorder characterized by hypertrophic cardiomyopathy and encephalopathy, and point to the presence of one or more other genes, perhaps in the copper delivery pathway, in this clinical phenotype.

+ To whom correspondence should be addressed. Tel: +1 514 398 1997; Fax: +1 514 398 1509; Email: eric@ericpc.mni.mcgill.ca


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