MT-CYB – Mitochondrial Disease

MT-CYB encodes the mitochondrially-encoded cytochrome b subunit of complex III of the oxidative phosphorylation chain (Gene Symbol). Pathogenic variants in MT-CYB disrupt electron transport at the quinol oxidation (Q_O) site, leading to impaired oxidative phosphorylation and multisystem mitochondrial disease (Disease Name).

Clinical Validity (Moderate)

Multiple independent studies have identified MT-CYB variants in patients with mitochondrial disease across diverse phenotypes including myopathy, encephalopathy, lactic acidosis, hearing impairment and cardiomyopathy. A large TTGE screen of 179 unrelated patients detected 71 heteroplasmic and 647 homoplasmic cytochrome b changes, with 68 novel variants shown to be deleterious by family segregation and biochemical correlation (PMID:12406974). Numerous single-case reports confirmed pathogenicity of both heteroplasmic (e.g., m.15635T>C homoplasmic in a neonate with polyvisceral failure) and heteroplasmic missense mutations (e.g., m.15615G>A (p.Gly290Asp) in adult-onset exercise intolerance) (PMID:19563916; PMID:8910895).

Genetic Evidence (Moderate)

Inheritance follows maternal (mitochondrial) transmission with variable heteroplasmy levels. Comprehensive patient surveys identified at least 179 probands harboring cytochrome b alterations with biochemical complex III deficiencies and clinical features of mitochondrial disease (PMID:12406974). Pathogenic variants span missense (e.g., G290D), nonsense (e.g., W135Ter), frameshift and rearrangement classes. Recurrent homoplasmic changes are rare; most mutations are private or family-specific. Population background sequencing reveals numerous homoplasmic polymorphisms of uncertain significance, underscoring the need for functional validation.

Functional Evidence (Moderate)

Yeast and transmitochondrial cybrid models recapitulate complex III defects caused by MT-CYB mutations. The G290D substitution reduces complex III activity, lowers cytochrome b levels and impairs respiratory growth (PMID:8910895). The analogous Arg318Pro mutation abolishes assembly of both complexes III and I, confirming structural interdependence (PMID:16008558). High-resolution structural and EPR analyses demonstrate that interface mutations (e.g., p.278Tyr>Cys) perturb ISP headgroup motion, enhance reactive oxygen species production, and impair supercomplex formation (PMID:23418307; PMID:27032290).

Conflicting Evidence

Large-scale mtDNA surveys reveal hundreds of homoplasmic MT-CYB variants with unclear pathogenicity. Some proposed disease-associated changes show high population frequency or lack functional impact, highlighting challenges in variant interpretation without biochemical confirmation.

Integration & Key Take-Home

MT-CYB mutations cause mitochondrial disease through loss of complex III function, with clinical presentations ranging from severe neonatal failure to adult-onset myopathy and cardiomyopathy. Functional assays and transmission studies are essential for variant classification. MT-CYB sequencing should be incorporated into diagnostic workflows for suspected mitochondrial disorders to guide clinical management and genetic counseling.

References

• Clinical chemistry • 2002 • Comprehensive scanning of the entire mitochondrial genome for mutations. PMID:12406974
• Molecular and cellular probes • 1996 • A novel gly290asp mitochondrial cytochrome b mutation linked to a complex III deficiency in progressive exercise intolerance. PMID:8910895
• Mitochondrion • 2009 • A neonatal polyvisceral failure linked to a de novo homoplasmic mutation in the mitochondrially encoded cytochrome b gene. PMID:19563916
• FEBS journal • 2005 • A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast. PMID:16008558
• Human molecular genetics • 2013 • The cytochrome b p.278Y>C mutation causative of a multisystem disorder enhances superoxide production and alters supramolecular interactions of respiratory chain complexes. PMID:23418307
• Biochimica et biophysica acta • 2016 • Mitochondrial disease-related mutations at the cytochrome b-iron-sulfur protein (ISP) interface. PMID:27032290

Evidence Based Scoring (AI generated)