Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis

Abstract

Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.

Mitochondrial disorders of the OXPHOS system

“…In the case of CYC1, two different missense mutations were present in two unrelated individuals showing a similar clinical course with cIII deficiency accompanied by recurrent metabolic crises and insulinresponsive hyperglycemia [159]. Defective UQCRFS1 has been deemed the cause of decreased cIII activity, lactic acidosis, cardiomyopathy, and alopecia totalis [160].…”

Host genetic effects in pneumonia

“… 31 Rare mutations in UQCRFS1 have been previously reported as the cause of a mitochondrial disorder (MIM: 618775). 32 Further, Uqcrfs1 deletion in mice abolishes mitochondrial reactive oxygen species that are required for antigen specific T cell responses, a hallmark of the adaptive immune response. 33 We did not observe replication of rs148218440 in BioVU non-MEGA EX AA ( Table 1 ), however we note that this analysis was underpowered to detect effect (n = 292 affected individuals and 1,145 control individuals, Table S4 ); UK Biobank did not have enough AA individuals with pneumonia to perform a replication analysis (n = 76 affected individuals and 9,272 control individuals, Table S5 ).…”

Identification of key pathways and genes in polycystic ovary syndrome via integrated bioinformatics analysis and prediction of small therapeutic molecules

“…The GO and pathway enrichment analysis was of great importance for interpreting the molecular mechanisms of the key cellular activities in PCOS. RPS5 [ 37 ], RBM3 [ 38 ], BAK1 [ 39 ], NDUFC2 [ 40 ], NDUFS4 [ 41 ], NDUFS5 [ 42 ], UQCRFS1 [ 43 ], COX6B1 [ 44 ], NDUFA13 [ 45 ], PRMT1 [ 46 ], RDX (radixin) [ 47 ], EPHB4 [ 48 ], SYNE2 [ 49 ], DNAH5 [ 50 ], NEDD4L [ 51 ], PDE4B [ 52 ] and CTNND1 [ 53 ] plays a critical role in the process of cardiovascular disease, but these genes might be linked with development of PCOS. Ostergaard et al [ 54 ], Zi et al [ 55 ], Kunej et al [ 56 ], Van der Schueren et al [ 57 ], Jin et al [ 58 ], Emdad et al [ 59 ], Liu et al [ 60 ], Scherag et al [ 61 ], Shi and Long [ 62 ], Sharma et al [ 63 ], Parente et al [ 64 ], Saint-Laurent et al [ 65 ] and Lee [ 66 ] demonstrated that over expression of COA3, PHB (prohibitin), UQCRC1, COX4I1, IFI27, MTDH (metadherin), S100A16, SDCCAG8, GLI2, NTN1, NLGN2, FGFR3 and PTPRN2 could cause obesity, but these genes might be involved in progression of PCOS.…”