UQCRC2 – Mitochondrial Complex III Deficiency

Mitochondrial Complex III deficiency is an autosomal recessive disorder characterized by neonatal‐onset metabolic decompensation including lactic acidosis, hyperammonemia, and ketosis. Complex III (ubiquinol–cytochrome c reductase) is composed of 11 subunits, and defects in nuclear‐encoded core proteins impair electron transport and supercomplex assembly. The gene UQCRC2 encodes the core protein II subunit essential for dimerization and stability of CIII.

Genetic evidence for UQCRC2 involvement derives from 5 unrelated probands ([PMID:23281071];[PMID:33865955];[PMID:37709555]) with homozygous or compound heterozygous missense variants. In a consanguineous Mexican family, three siblings homozygous for c.547C>T (p.Arg183Trp) presented with lactic acidosis, ketosis, and hyperammonemia in the neonatal period ([PMID:23281071]). A separate patient with severe encephalomyopathy harbored homozygous c.665G>C (p.Gly222Ala) ([PMID:33865955]), and one individual was compound heterozygous for c.437T>C (p.Phe146Ser) and c.1189G>A (p.Gly397Arg) with preserved neurodevelopment ([PMID:37709555]).

Segregation analysis in the first pedigree confirmed variant co-segregation in 2 additional affected siblings ([PMID:23281071]). No conflicting allele findings or alternative inheritance modes have been reported. All variants described are missense, and no recurrent or population‐specific founder alleles have yet been identified.

Functional assays in patient fibroblasts demonstrated markedly reduced CIII activity and impaired assembly of CI–CIII–CIV supercomplexes for both p.Arg183Trp and p.Gly222Ala variants. Incomplete subassemblies lacking UQCRC2 and UQCRC1 accumulated, and elevated mitochondrial protease CLPP indicated activation of protein quality control. Ectopic expression of wild‐type UQCRC2 rescued maximal respiration rate, confirming a loss‐of‐function mechanism ([PMID:23281071];[PMID:33865955]).

Collectively, the genetic and experimental data support a strong gene–disease association between UQCRC2 and Mitochondrial Complex III Deficiency. Analysis of UQCRC2 should be included in diagnostic gene panels for mitochondrial respiratory chain disorders.

References

• Human Mutation • 2013 • Mitochondrial complex III deficiency caused by a homozygous UQCRC2 mutation presenting with neonatal-onset recurrent metabolic decompensation. PMID:23281071
• Biochimica et biophysica acta. Molecular basis of disease • 2021 • Homozygous missense mutation in UQCRC2 associated with severe encephalomyopathy, mitochondrial complex III assembly defect and activation of mitochondrial protein quality control. PMID:33865955
• Cold Spring Harbor molecular case studies • 2023 • Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment. PMID:37709555

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