2. Academic Validation
  3. Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis

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

  • Am J Hum Genet. 2020 Jan 2;106(1):102-111. doi: 10.1016/j.ajhg.2019.12.005.
Mirjana Gusic 1,  Gudrun Schottmann 2,  René G Feichtinger 3,  Chen Du 4,  Caroline Scholz 4,  Matias Wagner 5,  Johannes A Mayr 3,  Chae-Young Lee 2,  Vicente A Yépez 6,  Norbert Lorenz 7,  Susanne Morales-Gonzalez 2,  Daan M Panneman 8,  Agnès Rötig 9,  Richard J T Rodenburg 8,  Saskia B Wortmann 10,  Holger Prokisch 1,  Markus Schuelke 11
Affiliations

Affiliations

  • 1 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany.
  • 2 Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health: NeuroCure Cluster of Excellence, 10117 Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health: Department of Neuropediatrics, 13353 Berlin, Germany.
  • 3 University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
  • 4 Institute of Human Genetics, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
  • 5 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 6 Department of Informatics, Technical University of Munich, 81371 Garching, Germany.
  • 7 Department of Pediatric Cardiology, Municipal Hospital Dresden, 01307 Dresden, Germany.
  • 8 Radboud Center for Mitochondrial Disorders, Department of Pediatrics, Radboud UMC, Nijmegen 6525, the Netherlands.
  • 9 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
  • 10 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany; University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
  • 11 Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health: NeuroCure Cluster of Excellence, 10117 Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health: Department of Neuropediatrics, 13353 Berlin, Germany. Electronic address: markus.schuelke@charite.de.
PMID: 31883641 DOI: 10.1016/j.ajhg.2019.12.005
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.

Keywords

Q-cycle; Rieske iron-sulfur protein; alopecia; cardiomyopathy; microscale respiratory; mitochondrial complex III deficiency; mitochondrial import sequence; mitochondriopathy; mutation.

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