EMBO Molecular Medicine (Dec 2021)
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‐Rodewald,
- Stefanie 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
Affiliations
- Silvia Vidali
- Institute of Human Genetics School of Medicine Technische Universität München Munich Germany
- Raffaele Gerlini
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Kyle Thompson
- Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Jill E Urquhart
- Manchester Centre for Genomic Medicine Manchester University NHS Foundation Trust Manchester UK
- Jana Meisterknecht
- Functional Proteomics Institute for Cardiovascular Physiology Faculty of Medicine Goethe University Frankfurt Frankfurt Germany
- Juan Antonio Aguilar‐Pimentel
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Oana V Amarie
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Lore Becker
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Catherine Breen
- Manchester Centre for Genomic Medicine Manchester University NHS Foundation Trust Manchester UK
- Julia Calzada‐Wack
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Nirav F Chhabra
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Yi‐Li Cho
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Patricia da Silva‐Buttkus
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- René G Feichtinger
- Department of Pediatrics University Hospital Salzburg Paracelsus Medical University Salzburg Salzburg Austria
- Kristine Gampe
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Lillian Garrett
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Kai P Hoefig
- Research Unit Molecular Immune Regulation Helmholtz Zentrum München German Research Center for Environmental Health Munich Germany
- Sabine M Hölter
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Elisabeth Jameson
- Manchester Centre for Genomic Medicine Manchester University NHS Foundation Trust Manchester UK
- Tanja Klein‐Rodewald
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Stefanie Leuchtenberger
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Susan Marschall
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Philipp Mayer‐Kuckuk
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Gregor Miller
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Manuela A Oestereicher
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Kristina Pfannes
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Birgit Rathkolb
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Jan Rozman
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Charlotte Sanders
- Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- Nadine Spielmann
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Claudia Stoeger
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Marten Szibor
- Faculty of Medicine and Health Technology Tampere University Tampere Finland
- Irina Treise
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- John H Walter
- Manchester Centre for Genomic Medicine Manchester University NHS Foundation Trust Manchester UK
- Wolfgang Wurst
- Institute of Developmental Genetics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Johannes A Mayr
- Department of Pediatrics University Hospital Salzburg Paracelsus Medical University Salzburg Salzburg Austria
- Helmut Fuchs
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Ulrich Gärtner
- Institute for Anatomy and Cell Biology Justus‐Liebig‐University of Giessen Giessen Germany
- Ilka Wittig
- Functional Proteomics Institute for Cardiovascular Physiology Faculty of Medicine Goethe University Frankfurt Frankfurt Germany
- Robert W Taylor
- Wellcome Centre for Mitochondrial Research Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK
- William G Newman
- Manchester Centre for Genomic Medicine Manchester University NHS Foundation Trust Manchester UK
- Holger Prokisch
- Institute of Human Genetics School of Medicine Technische Universität München Munich Germany
- Valerie Gailus‐Durner
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- Martin Hrabě de Angelis
- Institute of Experimental Genetics and German Mouse Clinic Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany
- DOI
- https://doi.org/10.15252/emmm.202114397
- Journal volume & issue
-
Vol. 13,
no. 12
pp. n/a – n/a
Abstract
Abstract 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.
Keywords