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Gusic, M. ; Schottmann, G.* ; Feichtinger, R.G.* ; Du, C.* ; Scholz, C.* ; Wagner, M. ; Mayr, J.A.* ; Lee, C.Y.* ; Yépez, V.A.* ; Lorenz, N.* ; Morales-Gonzalez, S.* ; Panneman, D.M.* ; Rötig, A.* ; Rodenburg, R.J.T.* ; Wortmann, S.B. ; Prokisch, H. ; Schuelke, M.*

Bi-allelic UQCRFS1 variants are associated with mitochondrial complex III deficiency, cardiomyopathy, and Alopecia Totalis.

Am. J. Hum. Genet. 106, 102-111 (2020)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Alopecia ; Cardiomyopathy ; Microscale Respiratory ; Mitochondrial Complex Iii Deficiency ; Mitochondrial Import Sequence ; Mitochondriopathy ; Mutation ; Q-cycle ; Rieske Iron-sulfur Protein; Iron-sulfur Protein; Respiratory-chain; Cytochrome-b; Bc(1) Complex; Homozygous Mutation; Gene; Manifestations; Encephalopathy; Architecture; Lyrm7/mzm1l
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Quellenangaben Volume: 106, Issue: 1, Pages: 102-111 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed