A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast - PubMed (original) (raw)

A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast

Emma L Blakely et al. FEBS J. 2005 Jul.

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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.

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