title: A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast.
abstract: Whereas the majority of disease-related mitochondrial DNA mutations exhibit significant biochemical and clinical heterogeneity, mutations within the mitochondrially encoded human cytochrome b gene (MTCYB) are almost exclusively associated with isolated complex III deficiency in muscle and a clinical presentation involving exercise intolerance. Recent studies have shown that a small number of MTCYB mutations are associated with a combined enzyme complex defect involving both complexes I and III, on account of the fact that an absence of assembled complex III results in a dramatic loss of complex I, confirming a structural dependence between these two complexes. We present the biochemical and molecular genetic studies of a patient with both muscle and brain involvement and a severe reduction in the activities of both complexes I and III in skeletal muscle due to a novel mutation in the MTCYB gene that predicts the substitution (Arg318Pro) of a highly conserved amino acid. Consistent with the dramatic biochemical defect, Western blotting and BN-PAGE experiments demonstrated loss of assembled complex I and III subunits. Biochemical studies of the equivalent amino-acid substitution (Lys319Pro) in the yeast enzyme showed a loss of enzyme activity and decrease in the steady-state level of bc1 complex in the mutant confirming pathogenicity.
authors: Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, UK.
authors: Emma L
authors: EL
authors: Blakely
authors: Anna L
authors: AL
authors: Mitchell
authors: Nicholas
authors: N
authors: Fisher
authors: Brigitte
authors: B
authors: Meunier
authors: Leo G
authors: LG
authors: Nijtmans
authors: Andrew M
authors: AM
authors: Schaefer
authors: Margaret J
authors: MJ
authors: Jackson
authors: Douglass M
authors: DM
authors: Turnbull
authors: Robert W
authors: RW
authors: Taylor
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001706:Biopsy; D045303:Cytochromes b / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D019791:Guanidine / Q000378:metabolism; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009132:Muscles / Q000201:enzymology; D009154:Mutation / Q000235:genetics*; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D021122:Protein Subunits; D045303:Cytochromes b; D001120:Arginine; D019791:Guanidine