CYCS – Thrombocytopenia 4

Thrombocytopenia 4 (THC4) is an autosomal dominant mild thrombocytopenia caused by heterozygous missense variants in CYCS, the gene encoding mitochondrial cytochrome c, a key component of the electron transport chain and the intrinsic apoptotic pathway. Initial discovery in a New Zealand pedigree identified the G41S variant, and subsequent reports described a Y48H mutation in an Italian family, all with normal platelet morphology but reduced counts and no severe bleeding ((PMID:24326104)).

A recent multi-center study described six additional families of Italian origin harboring five different CYCS missense variants in 22 affected individuals, establishing autosomal dominant inheritance with full co-segregation of variants and phenotype ((PMID:38815995)). All variants are missense changes located in conserved regions of the protein, including the heme-binding loops. The most recurrent variants are c.124G>A (p.Gly42Ser) and c.145T>C (p.Tyr49His), observed in multiple kindreds. Segregation analysis confirmed that these variants track with thrombocytopenia in 22 relatives across six families ((PMID:38815995)).

Functional assays in yeast and mouse cellular models of both G41S and Y48H variants demonstrated impaired oxidative growth, decreased respiratory activity, and increased apoptotic rate, mirroring the reduction of platelet production seen in patients ((PMID:24326104)). Structural and biochemical studies indicate that these mutations increase cytochrome c peroxidase activity via conformational alterations in the 40–57 Ω-loop and the Met80-containing Ω-loop, promoting a pentacoordinate heme state conducive to apoptosis. No studies to date dispute the CYCS–THC4 association.

Integration of genetic and experimental evidence supports a strong clinical validity for CYCS in THC4. Genetic testing for CYCS missense variants is warranted in patients with unexplained mild thrombocytopenia. Functional assays measuring apoptotic and bioenergetic alterations provide additional confirmation of variant pathogenicity. Key take-home: CYCS missense variants cause autosomal dominant thrombocytopenia 4 by augmenting cytochrome c apoptotic activity and impairing mitochondrial respiration, guiding molecular diagnosis and informing future therapeutic exploration.

References

• Biochimica et biophysica acta • 2014 • Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics. PMID:24326104
• British journal of haematology • 2024 • Thrombocytopenia 4 (THC4): Six novel families with mutations of the cytochrome c gene. PMID:38815995

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