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

0559909 - ÚMG 2023 RIV GB eng J - Journal Article
Vidali, S. - Rozman, Jan - Spielmann, N. - Gerlini, R. - Thompson, K. - Urquhart, J. E. - Meisterknech, J. - Aguilar-Pimentel, J. A. - Amarie, O. V. - Becker, L. - Breen, C. - Calzada-Wack, J. - Chhabra, N. V. - Cho, Y. L. - Da Silva-Buttkus, P. - Feichtinge, R. G. - Gampe, K. - Garrett, L. - Hoefig, K. P. - Hölter, S. M. - Jameson, E. - Klein-Rodewald, T. - Leuchtenberger, S. - Marschall, S. - Gailus-Durne, V. … Total 44 authors
Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes.
EMBO Molecular Medicine. Roč. 13, č. 12 (2021), č. článku e14397. ISSN 1757-4676. E-ISSN 1757-4684
Institutional support: RVO:68378050
Keywords : complex III * mitochondrial disease * mouse model * oxphos * uqcrh
OECD category: Immunology
Impact factor: 14.005, year: 2021
Method of publishing: Open access
https://www.embopress.org/doi/full/10.15252/emmm.202114397

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.
Permanent Link: https://hdl.handle.net/11104/0333033