UQCRFS1 – Mitochondrial Complex III Deficiency

Biallelic variants in UQCRFS1 cause Mitochondrial Complex III Deficiency, a rare autosomal recessive respiratory chain disorder. A total of three unrelated probands have been reported, each harboring two pathogenic UQCRFS1 alleles, with no extended family segregation described to date.

The inheritance is autosomal recessive, with two affected individuals described by Khan et al. presenting with early-onset lactic acidosis and alopecia totalis (PMID:31883641) and a third UDN participant reported by Smith et al. (PMID:39421685). Variant classes include missense, nonsense, and splice-site changes. Notable alleles comprise c.41T>A (p.Val14Asp) and c.610C>T (p.Arg204Ter) in one family (PMID:31883641) and the recurrent splice acceptor c.215-1G>C (p.Val72_Thr81del10) in another (PMID:39421685).

Functional assays in patient-derived fibroblasts demonstrate markedly reduced complex III activity, low UQCRFS1 protein abundance, impaired mitochondrial import, and defective assembly of the Rieske subunit. Quantitative cellular proteomics confirmed a specific loss of the Rieske iron–sulfur protein (PMID:31883641).

Rescue experiments via lentiviral overexpression of wild-type UQCRFS1 fully restored complex III activity and normalized respiratory chain function, establishing haploinsufficiency as the pathogenic mechanism (PMID:31883641).

Clinically, affected individuals present with lactic acidosis (HP:0003128), hypertrophic cardiomyopathy, and alopecia totalis, expanding the phenotypic spectrum of complex III deficiency. Deep phenotyping combined with genomic sequencing allows definitive diagnosis and informs management of mitochondrial respiratory chain disorders.

Key Take-home: UQCRFS1 should be included in diagnostic panels for early-onset mitochondrial complex III deficiency, with functional complementation assays available to confirm pathogenicity.

References

• American journal of human genetics | 2020 | Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis. PMID:31883641
• Rare (Amsterdam, Netherlands) | 2024 | Dual diagnosis of UQCRFS1-related mitochondrial complex III deficiency and recessive GJA8-related cataracts. PMID:39421685

Evidence Based Scoring (AI generated)