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

ABSTRACT: 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.

SUBMITTER: Vidali S

PROVIDER: S-EPMC8649870 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Vidali Silvia S Gerlini Raffaele R Thompson Kyle K Urquhart Jill E JE Meisterknecht Jana J Aguilar-Pimentel Juan Antonio JA Amarie Oana V OV Becker Lore L Breen Catherine C Calzada-Wack Julia J Chhabra Nirav F NF Cho Yi-Li YL da Silva-Buttkus Patricia P Feichtinger René G RG Gampe Kristine K Garrett Lillian L Hoefig Kai P KP Hölter Sabine M SM Jameson Elisabeth E Klein-Rodewald Tanja T Leuchtenberger Stefanie S Marschall Susan S Mayer-Kuckuk Philipp P Miller Gregor G Oestereicher Manuela A MA Pfannes Kristina K Rathkolb Birgit B Rozman Jan J Sanders Charlotte C Spielmann Nadine N Stoeger Claudia C Szibor Marten M Treise Irina I Walter John H JH Wurst Wolfgang W Mayr Johannes A JA Fuchs Helmut H Gärtner Ulrich U Wittig Ilka I Taylor Robert W RW Newman William G WG Prokisch Holger H Gailus-Durner Valerie V Hrabě de Angelis Martin M

EMBO molecular medicine 20211108 12

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 ...[more]

PMID: 34750991

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Project description:ObjectiveDuchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset.MethodsThis cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies.ResultsThe series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors.InterpretationWe confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-806.

Dataset Information

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

Publications

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

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