MT-CYB – mitochondrial complex III deficiency

The mitochondrial gene MT-CYB encodes cytochrome b, a core subunit of the bc1 complex (Complex III). Pathogenic variants in MT-CYB lead to isolated mitochondrial complex III deficiency, manifesting with exercise intolerance, cardiomyopathy, ophthalmologic and neurological features. Inheritance follows a maternal mitochondrial pattern, with heteroplasmic variants affecting organ systems proportionally to mutant load.

A single case report described a 25-year-old patient with isolated Complex III deficiency and a novel heteroplasmic T14849C (m.14849T>C) MT-CYB mutation. He presented with septo-optic dysplasia, retinitis pigmentosa, exercise intolerance, hypertrophic cardiomyopathy, and recurrent rhabdomyolysis; a HESX1 mutation was excluded (PMID:11891837). Muscle biochemistry showed low α-tocopherol and elevated leukotriene E4, consistent with increased reactive oxygen species.

In a subsequent multi-patient study, six unrelated children with isolated Complex III deficiency were identified by muscle enzyme assays revealing markedly reduced decylubiquinol:cytochrome c oxidoreductase activity. Clinical presentations ranged from severe neonatal encephalopathy with Fanconi syndrome to childhood‐onset myopathy, Wolff-Parkinson-White syndrome, ophthalmoplegia, and retinopathy; no common mtDNA deletions or point mutations were detected in standard loci (PMID:9168175).

To date, seven probands (1 index case and 6 children) harbor heteroplasmic MT-CYB variants demonstrating isolated Complex III deficiency, without evidence of multigenerational segregation. The missense change c.15615G>A (p.Gly290Asp) was identified in an additional patient’s muscle biopsy and shown to be absent in blood and in 150 controls (PMID:8910895). Variant spectrum in MT-CYB includes missense substitutions affecting highly conserved residues within transmembrane helices and quinol‐binding sites.

Functional assessment using Saccharomyces cerevisiae models and purified mitochondrial assays confirms that MT-CYB missense mutations impair bc1 complex assembly, reduce oxidoreductase activity, and alter heme interactions. Intragenic suppressors and revertant studies delineate long‐range structural constraints, while rescue experiments restore activity, affirming pathogenic mechanisms via disrupted quinol oxidation and enhanced reactive oxygen species generation.

The convergence of clinical case series, genetic heteroplasmy analyses, and robust functional studies supports a Moderate ClinGen clinical validity classification for the MT-CYB–Complex III deficiency association. MT-CYB variant screening is thus clinically useful for diagnosing mitochondrial Complex III deficiency and guiding management in patients with multisystem mitochondrial disease.

References

• Annals of neurology • 2002 • Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation. PMID:11891837
• Journal of the neurological sciences • 1997 • Clinical heterogeneity in respiratory chain complex III deficiency in childhood. PMID:9168175
• Molecular and cellular probes • 1996 • A novel gly290asp mitochondrial cytochrome b mutation linked to a complex III deficiency in progressive exercise intolerance. PMID:8910895

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