title: Novel mutations in SCO1 as a cause of fatal infantile encephalopathy and lactic acidosis.
abstract: Isolated cytochrome c oxidase (COX) deficiency is a common cause of mitochondrial disease, yet its genetic basis remains unresolved in many patients. Here, we identified novel compound heterozygous mutations in SCO1 (p.M294V, p.Val93*) in one such patient with fatal encephalopathy. The patient lacked the severe hepatopathy (p.P174L) or hypertrophic cardiomyopathy (p.G132S) observed in previously reported SCO1 cases, so we investigated whether allele-specific defects in SCO1 function might underlie the genotype-phenotype relationships. Fibroblasts expressing p.M294V had a relatively modest decrease in COX activity compared with those expressing p.P174L, whereas both SCO1 lines had marked copper deficiencies. Overexpression of known pathogenic variants in SCO1 fibroblasts showed that p.G132S exacerbated the COX deficiency, whereas COX activity was partially or fully restored by p.P174L and p.M294V, respectively. These data suggest that the clinical phenotypes in SCO1 patients might reflect the residual capacity of the pathogenic alleles to perform one or both functions of SCO1.
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Scot C
authors.initials: SC
authors.lastname: Leary
authors.forename: Hana
authors.initials: H
authors.lastname: Antonicka
authors.forename: Florin
authors.initials: F
authors.lastname: Sasarman
authors.forename: Woranontee
authors.initials: W
authors.lastname: Weraarpachai
authors.forename: Paul A
authors.initials: PA
authors.lastname: Cobine
authors.forename: Min
authors.initials: M
authors.lastname: Pan
authors.forename: Garry K
authors.initials: GK
authors.lastname: Brown
authors.forename: Ruth
authors.initials: R
authors.lastname: Brown
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Kevin C H
authors.initials: KC
authors.lastname: Ha
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000595:Amino Acid Sequence; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D023061:Gene Order; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009154:Mutation; D009849:Olivopontocerebellar Atrophies / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D008565:Membrane Proteins; D018832:Molecular Chaperones; C489345:SCO1 protein, human
keywords: SCO1; copper; cytochrome c oxidase; metallochaperone; mitochondrial diseases