TY - JOUR
T1 - Characterising a homozygous two-exon deletion in UQCRH
T2 - comparing human and mouse phenotypes
AU - Vidali, Silvia
AU - Gerlini, Raffaele
AU - Thompson, Kyle
AU - Urquhart, Jill E.
AU - Meisterknecht, Jana
AU - Aguilar-Pimentel, Juan Antonio
AU - Amarie, Oana V.
AU - Becker, Lore
AU - Breen, Catherine
AU - Calzada-Wack, Julia
AU - Chhabra, Nirav F.
AU - Cho, Yi Li
AU - da Silva-Buttkus, Patricia
AU - Feichtinger, René G.
AU - Gampe, Kristine
AU - Garrett, Lillian
AU - Hoefig, Kai P.
AU - Hölter, Sabine M.
AU - Jameson, Elisabeth
AU - Klein-Rodewald, Tanja
AU - Leuchtenberger, Stefanie
AU - Marschall, Susan
AU - Mayer-Kuckuk, Philipp
AU - Miller, Gregor
AU - Oestereicher, Manuela A.
AU - Pfannes, Kristina
AU - Rathkolb, Birgit
AU - Rozman, Jan
AU - Sanders, Charlotte
AU - Spielmann, Nadine
AU - Stoeger, Claudia
AU - Szibor, Marten
AU - Treise, Irina
AU - Walter, John H.
AU - Wurst, Wolfgang
AU - Mayr, Johannes A.
AU - Fuchs, Helmut
AU - Gärtner, Ulrich
AU - Wittig, Ilka
AU - Taylor, Robert W.
AU - Newman, William G.
AU - Prokisch, Holger
AU - Gailus-Durner, Valerie
AU - Hrabě de Angelis, Martin
N1 - Funding Information:
This study was supported by a German Federal Ministry of Education and Research (BMBF, Bonn, Germany) grant to the German Network for Mitochondrial Disorders (mitoNET, 01GM1906D to IW); by the German BMBF and Horizon2020 through the E‐Rare project GENOMIT (01GM1920A to HP); and Austrian Science Fund (FWF) (I 4695‐B to JAM); by the Deutsche Forschungsgemeinschaft: SFB 815/Z1 (IW); and by the Cardio Pulmonary Institute (CPI) of the DFG (EXC2026 to IW), by the German Federal Ministry of Education and Research (Infrafrontier 01KX1012 to MHdA), the German Center for Diabetes Research (DZD) (MHdA). RWT is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Foundation (MRC) International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation and the Newcastle upon Tyne Hospitals NHS Foundation Trust (Newcastle upon Tyne Hospitals NHS Trust) who fund the “Rare Mitochondrial Disorders of Adults and Children” Diagnostic Service in Newcastle upon Tyne. CS was supported by a Vacation Scholarship from the British inherited Metabolic Disease Group. WGN is supported by Action Medical Research (AMR) (GN2494) and NIHR BRC IS‐BRC‐1215‐20007. We thank the GMC technicians and animal caretakers for their expert technical assistance. Open Access funding enabled and organized by Projekt DEAL.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - complex III
KW - mitochondrial disease
KW - mouse model
KW - OXPHOS
KW - UQCRH
U2 - 10.15252/emmm.202114397
DO - 10.15252/emmm.202114397
M3 - Article
AN - SCOPUS:85118626029
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 12
M1 - e14397
ER -