SDHC – Mitochondrial Disease

Biallelic inactivation of SDHC, encoding the membrane-anchoring subunit of mitochondrial complex II, disrupts succinate oxidation to fumarate and electron transfer to ubiquinone, resulting in isolated complex II deficiency and mitochondrial disease (leukodystrophy, Leigh syndrome) (PMID:24781757). Although no SDHC-specific cases have yet been reported, autosomal-recessive mutations in SDHA, SDHB and SDHD cause overlapping mitochondrial phenotypes, supporting an analogous role for SDHC. Functional modeling of the SDHC p.Arg72Gly homolog in yeast (c.214C>G (p.Arg72Gly)) revealed markedly reduced ubiquinone reductase activity, elevated superoxide production and succinate accumulation, consistent with complex II dysfunction (PMID:17636259).

Given mechanistic concordance across SDHx genes and robust functional data, SDHC is plausibly implicated in mitochondrial disease, but current case-level genetic evidence is limited. Screening for SDHC variants should be considered in autosomal-recessive mitochondrial disease gene panels. Key take-home: SDHC contributes critically to complex II assembly and function, warranting inclusion in diagnostic testing for mitochondrial disease.

References

• European journal of human genetics • 2015 • SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors PMID:24781757
• The Journal of Biological Chemistry • 2007 • Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate PMID:17636259

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