Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes

Silvia Vidali, Raffaele Gerlini, Kyle Thompson, Jill E. Urquhart, Jana Meisterknecht, Juan Antonio Aguilar-Pimentel, Oana V. Amarie, Lore Becker, Catherine Breen, Julia Calzada-Wack, Nirav F. Chhabra, Yi Li Cho, Patricia da Silva-Buttkus, René G. Feichtinger, Kristine Gampe, Lillian Garrett, Kai P. Hoefig, Sabine M. Hölter, Elisabeth Jameson, Tanja Klein-RodewaldStefanie Leuchtenberger, Susan Marschall, Philipp Mayer-Kuckuk, Gregor Miller, Manuela A. Oestereicher, Kristina Pfannes, Birgit Rathkolb, Jan Rozman, Charlotte Sanders, Nadine Spielmann, Claudia Stoeger, Marten Szibor, Irina Treise, John H. Walter, Wolfgang Wurst, Johannes A. Mayr, Helmut Fuchs, Ulrich Gärtner, Ilka Wittig, Robert W. Taylor, William G. Newman, Holger Prokisch, Valerie Gailus-Durner, Martin Hrabě de Angelis

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Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh−/−), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh−/− mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh−/− mouse is a valuable model for future studies of human CIII deficiency.

Original languageEnglish
Article numbere14397
JournalEMBO Molecular Medicine
Issue number12
Early online dateNov 2021
Publication statusPublished - Dec 2021
Publication typeA1 Journal article-refereed


  • complex III
  • mitochondrial disease
  • mouse model

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Molecular Medicine


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