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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

30102 - Immunology

Projekt

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Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

EMBO Molecular Medicine

ISSN

1757-4676

e-ISSN

1757-4684

Svazek periodika

13

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

19

Strana od-do

e14397

Kód UT WoS článku

000715894100001

EID výsledku v databázi Scopus

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