Open AccessCharacterising a homozygous two‐exon deletion in UQCRH : comparing human and mouse phenotypes
Author(s) -
Vidali Silvia,
Gerlini Raffaele,
Thompson Kyle,
Urquhart Jill E,
Meisterknecht Jana,
AguilarPimentel Juan Antonio,
Amarie Oana V,
Becker Lore,
Breen Catherine,
CalzadaWack Julia,
Chhabra Nirav F,
Cho YiLi,
da SilvaButtkus Patricia,
Feichtinger René G,
Gampe Kristine,
Garrett Lillian,
Hoefig Kai P,
Hölter Sabine M,
Jameson Elisabeth,
KleinRodewald Tanja,
Leuchtenberger Stefanie,
Marschall Susan,
MayerKuckuk Philipp,
Miller Gregor,
Oestereicher Manuela A,
Pfannes Kristina,
Rathkolb Birgit,
Rozman Jan,
Sanders Charlotte,
Spielmann Nadine,
Stoeger Claudia,
Szibor Marten,
Treise Irina,
Walter John H,
Wurst Wolfgang,
Mayr Johannes A,
Fuchs Helmut,
Gärtner Ulrich,
Wittig Ilka,
Taylor Robert W,
Newman William G,
Prokisch Holger,
GailusDurner Valerie,
Hrabě de Angelis Martin
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114397
Subject(s) - phenotype , lactic acidosis , exon , biology , failure to thrive , genetics , mutation , compound heterozygosity , protein subunit , genetic heterogeneity , gene , biochemistry
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 (S XL ), 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.