A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast.
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.
Blakely
Emma L
EL
Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, UK.
Mitchell
Anna L
AL
Fisher
Nicholas
N
Meunier
Brigitte
B
Nijtmans
Leo G
LG
Schaefer
Andrew M
AM
Jackson
Margaret J
MJ
Turnbull
Douglass M
DM
Taylor
Robert W
RW
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*
D004272:DNA, Mitochondrial; D021122:Protein Subunits; D045303:Cytochromes b; D001120:Arginine; D019791:Guanidine