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CYC1 encodes cytochrome c1, a core subunit of mitochondrial complex III. Biallelic pathogenic variants in CYC1 cause a nuclear complex III deficiency, a form of mitochondrial disease characterized by impaired electron transfer and disrupted oxidative phosphorylation. Affected individuals present with early-onset metabolic crises, including lactic acidosis, hyperammonemia, ketoacidosis, and insulin-responsive hyperglycemia.
The first series was reported in JIMD Reports describing a neonate with severe ketoacidosis, hyperlactatemia, hyperammonemia, and hyperglycemia; trio WES identified a homozygous c.643C>T (p.Leu215Phe) variant in CYC1 ([PMID:27074787]). This substitution was previously observed in two unrelated patients (one of Sri Lankan origin) with concordant phenotypes and absent complex III activity ([PMID:27074787]).
A subsequent report in Mitochondrion detailed a consanguineous Iranian family in which a 10-year-old girl presented with recurrent visual loss and optic nerve enhancement mimicking demyelination. Sanger sequencing confirmed segregation of a novel homozygous c.949C>T (p.Arg317Trp) variant in CYC1 with disease, and in silico modeling predicted destabilization of cytochrome c1 structure ([PMID:34252606]). Parents were heterozygous carriers and asymptomatic, consistent with autosomal recessive inheritance.
To date, four unrelated probands harbor biallelic missense CYC1 variants: p.Leu215Phe in three patients and p.Arg317Trp in one. No loss-of-function or splice variants have been reported. All missense changes are absent from population databases, predicted deleterious by in silico tools, and segregate with disease in consanguineous families. No additional affected relatives beyond probands have been documented.
Functional evidence arises from yeast ortholog studies demonstrating that residues equivalent to human Leu215 and Arg317 are critical for thermodynamic stability and heme-ligand interactions. Mutagenesis of yeast iso-1-cytochrome c alters hydrogen-bond networks and reduces protein stability, supporting a haploinsufficiency or destabilizing mechanism. Computational modeling of p.Arg317Trp further corroborates perturbation of active-site geometry. However, direct functional assays in patient-derived cells remain to be performed.
Integration of genetic and experimental findings supports a moderate level of clinical validity. Biallelic CYC1 missense variants segregate with a consistent mitochondrial disease phenotype across four probands, with biochemical confirmation of complex III deficiency. Yeast model and computational data highlight error-intolerant domains in cytochrome c1. Additional studies, including patient cell assays, are warranted to achieve definitive classification. Key Take-home: CYC1 sequencing should be prioritized in infants and children presenting with unexplained metabolic crises or optic neuropathy suggestive of complex III deficiency.
Gene–Disease AssociationModerate4 unrelated probands with biallelic missense CYC1 variants, AR inheritance, consistent biochemical phenotype Genetic EvidenceModerateFour probands with homozygous missense variants absent in controls; segregation in consanguineous families Functional EvidenceLimitedYeast ortholog mutagenesis and computational modeling indicate destabilizing effects but lack direct patient cell assays |