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

First Author	Vidali S	Year	2021
Journal	EMBO Mol Med	Volume	13
Issue	12	Pages	e14397
PubMed ID	34750991	Mgi Jnum	J:317737
Mgi Id	MGI:6841380	Doi	10.15252/emmm.202114397
Citation	Vidali S, et al. (2021) Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes. EMBO Mol Med 13(12):e14397

abstractText

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.

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