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UQCRB – Mitochondrial Complex III Deficiency, Nuclear Type 3

UQCRB encodes the ubiquinol-cytochrome c reductase binding protein, a core subunit of mitochondrial complex III. Biallelic pathogenic variants in UQCRB cause Mitochondrial Complex III Deficiency, Nuclear Type 3, an autosomal recessive disorder. To date, only 2 unrelated probands have been reported with homozygous or compound heterozygous UQCRB variants presenting with recurrent neonatal and childhood hypoglycemia, lactic acidosis, metabolic acidosis, tachypnea, abdominal pain, vomiting, and fever (PMID:35221877). In the index case, whole‐exome sequencing revealed a homozygous c.309_313del (p.Glu104ArgfsTer10) frameshift variant leading to premature termination of UQCRB, with clinical onset on day 1 of life and seven subsequent episodes of metabolic decompensation by age 10 (PMID:35221877).

Saccharomyces cerevisiae functional assays targeting conserved acidic residues in the Qcr7 ortholog demonstrate that D47G and D47N mutants exhibit defective assembly of the cytochrome bc1 complex and reduced ATP synthesis, supporting a loss-of-function mechanism analogous to human truncating variants (PMID:11556807). The convergence of a limited number of probands with consistent clinical features and supportive model organism data warrants a Limited classification for this gene–disease relationship. Further case identification and segregation studies are needed to elevate clinical validity. Key take-home: UQCRB loss-of-function variants should be considered in neonates with unexplained hypoglycemia and lactic acidosis after exclusion of common metabolic etiologies.

References

  • Molecular syndromology | 2022 | A Patient with Recurrent Severe Hypoglycemic Attacks and Mitochondrial Complex III Deficiency, Nuclear Type 3: a Novel UQCRB Variant. PMID:35221877
  • Archives of biochemistry and biophysics | 2001 | The functional role of conserved acidic residues of the Qcr7 protein of the cytochrome bc(1) complex in Saccharomyces cerevisiae. PMID:11556807

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

2 unrelated probands with homozygous frameshift variant c.309_313delAGAAA (p.Glu104ArgfsTer10) segregating recessively (PMID:35221877); limited case series

Genetic Evidence

Limited

2 probands with biallelic loss-of-function UQCRB variants, reaching minimal supporting level

Functional Evidence

Moderate

Site-directed mutagenesis of yeast Qcr7 acidic residues demonstrates defective complex III assembly and reduced ATP synthesis, modeling human loss-of-function (PMID:11556807)