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Vidali, S. ; Gerlini, R. ; Thompson, K.* ; Urquhart, J.E.* ; Meisterknecht, J.* ; Aguilar-Pimentel, J.A. ; Amarie, O.V. ; Becker, L. ; Breen, C.* ; Calzada-Wack, J. ; Chhabra, N.F. ; Cho, Y.-L. ; da Silva Buttkus, P. ; Feichtinger, R.G.* ; Gampe, K. ; Garrett, L. ; Hoefig, K.P. ; Hölter, S.M. ; Jameson, E.* ; Klein-Rodewald, T. ; Leuchtenberger, S. ; Marschall, S. ; Mayer-Kuckuk, P. ; Miller, G. ; Oestereicher, M.A. ; Pfannes, K. ; Rathkolb, B. ; Rozman, J. ; Sanders, C.* ; Spielmann, N. ; Stöger, C. ; Szibor, M.* ; Treise, I. ; Walter, J.H.* ; Wurst, W. ; Mayr, J.A.* ; Fuchs, H. ; Gärtner, U.* ; Wittig, I.* ; Taylor, R.W.* ; Newman, W.G.* ; Prokisch, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M.

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

EMBO Mol. Med.:e14397 (2021)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Complex Iii ; Mitochondrial Disease ; Mouse Model ; Oxphos ; Uqcrh; Complex-iii Deficiency; Mitochondrial-dna; Gracile Syndrome; Lactic-acidosis; Mutation; Patient; Disease; Gene; Identification; Lyrm7/mzm1l
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Quellenangaben Volume: , Issue: , Pages: , Article Number: e14397 Supplement: ,
Publisher Wiley
Publishing Place Chichester
Reviewing status Peer reviewed
Grants Lily Foundation
Austrian Science Fund (FWF)
Deutsche Forschungsgemeinschaft (DFG)
UKRI | MRC | Medical Research Foundation
Action Medical Research (AMR)
NIHR Bristol Biomedical Research Centre (Bristol BRC)
Newcastle upon Tyne Hospitals NHS Foundation Trust (Newcastle upon Tyne Hospitals NHS Trust)
Mitochondrial Disease Patient Cohort (UK)
German Center for Diabetes Research (DZD)