Characterising a homozygous two-exon deletion in UQCRH : comparing human and mouse phenotypes
Vidali, Silvia; Gerlini, Raffaele; Thompson, Kyle; Urquhart, Jill E.; Meisterknecht, Jana; Aguilar-Pimentel, Juan Antonio; Amarie, Oana V.; Becker, Lore; Breen, Catherine; Calzada-Wack, Julia; Chhabra, Nirav F.; Cho, Yi Li; da Silva-Buttkus, Patricia; Feichtinger, René G.; Gampe, Kristine; Garrett, Lillian; Hoefig, Kai P.; Hölter, Sabine M.; Jameson, Elisabeth; Klein-Rodewald, Tanja; Leuchtenberger, Stefanie; Marschall, Susan; Mayer-Kuckuk, 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; Gailus-Durner, Valerie; Hrabě de Angelis, Martin (2021-12)
Vidali, Silvia
Gerlini, Raffaele
Thompson, Kyle
Urquhart, Jill E.
Meisterknecht, Jana
Aguilar-Pimentel, Juan Antonio
Amarie, Oana V.
Becker, Lore
Breen, Catherine
Calzada-Wack, Julia
Chhabra, Nirav F.
Cho, Yi Li
da Silva-Buttkus, Patricia
Feichtinger, René G.
Gampe, Kristine
Garrett, Lillian
Hoefig, Kai P.
Hölter, Sabine M.
Jameson, Elisabeth
Klein-Rodewald, Tanja
Leuchtenberger, Stefanie
Marschall, Susan
Mayer-Kuckuk, 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
Gailus-Durner, Valerie
Hrabě de Angelis, Martin
12 / 2021
e14397
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202111248631
https://urn.fi/URN:NBN:fi:tuni-202111248631
Kuvaus
Peer reviewed
Tiivistelmä
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.
Kokoelmat
- TUNICRIS-julkaisut [16983]