UQCRC2 – Mitochondrial Disease

Biallelic variants in UQCRC2, encoding core protein II of mitochondrial complex III, have been implicated in autosomal recessive mitochondrial disease. The clinical validity of this association is classified as Moderate by ClinGen, supported by four probands from three unrelated families, segregation with two additional affected siblings, and concordant functional data.

Genetic evidence stems from case reports and series. The inheritance mode is autosomal recessive with segregation of the same homozygous variant in a consanguineous pedigree showing two additional affected siblings (PMID:23281071). In total, four probands have been described: one with recurrent neonatal liver failure and lactic acidosis (PMID:28275242), three siblings with neonatal-onset metabolic decompensation (PMID:23281071), one case of severe encephalomyopathy (PMID:33865955), and one compound heterozygote with normal neurodevelopment (PMID:37709555).

The recurrent missense variant c.547C>T (p.Arg183Trp) disrupts the hydrophobic core at the UQCRC2 homodimer interface and was observed in a neonatal patient with lactic acidosis, hypoglycemia and liver failure (PMID:28275242; PMID:23281071). Structural modeling predicted destabilization of complex III, consistent with impaired assembly in patient fibroblasts.

A distinct homozygous variant, c.665G>C (p.Gly222Ala), identified in a severe encephalomyopathy patient, led to accumulation of CIII subassemblies lacking UQCRC2 and UQCRC1, activation of mitochondrial CLPP protease, diminished complex I levels, and impaired electron flux; ectopic wild-type UQCRC2 rescued maximal respiration (PMID:33865955).

Compound heterozygosity for c.437T>C (p.Phe146Ser) and c.1189G>C (p.Gly397Arg) in a patient with lactic acidosis, hyperammonemia and hypoglycemia but normal neurodevelopment further expands the phenotype and variant spectrum (PMID:37709555).

Mechanistically, UQCRC2 variants disrupt complex III assembly leading to respiratory chain deficiency. Functional assays across multiple studies demonstrate concordant enzyme defects and rescue by wild-type complementation. Additional evidence beyond ClinGen scoring includes detailed proteomic analyses of supercomplex architecture. Key Take-home: Biallelic UQCRC2 variants cause autosomal recessive mitochondrial disease marked by complex III deficiency, with robust functional assays supporting diagnostic interpretation.

References

• Journal of human genetics • 2017 • UQCRC2 mutation in a patient with mitochondrial complex III deficiency causing recurrent liver failure, lactic acidosis and hypoglycemia. PMID:28275242
• 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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