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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F21%3A00559909" target="_blank" >RIV/68378050:_____/21:00559909 - isvavai.cz</a>
Result on the web
<a href="https://www.embopress.org/doi/full/10.15252/emmm.202114397" target="_blank" >https://www.embopress.org/doi/full/10.15252/emmm.202114397</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.15252/emmm.202114397" target="_blank" >10.15252/emmm.202114397</a>

Result language
angličtina
Original language name
Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30102 - Immunology

Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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