OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect.

Autor: Thompson K; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Mai N; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Oláhová M; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Scialó F; Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK., Formosa LE; Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia., Stroud DA; Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Vic., Australia., Garrett M; Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia., Lax NZ; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Robertson FM; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Jou C; Pathology Department, Hospital Sant Joan de Déu, CIBERER, Barcelona, Spain., Nascimento A; Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, CIBERER - ISCIII, Barcelona, Spain., Ortez C; Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, CIBERER - ISCIII, Barcelona, Spain., Jimenez-Mallebrera C; Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, CIBERER - ISCIII, Barcelona, Spain., Hardy SA; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., He L; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Brown GK; Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Marttinen P; Institute of Biotechnology, University of Helsinki, Helsinki, Finland., McFarland R; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Sanz A; Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK., Battersby BJ; Institute of Biotechnology, University of Helsinki, Helsinki, Finland., Bonnen PE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Ryan MT; Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Vic., Australia., Chrzanowska-Lightowlers ZM; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Lightowlers RN; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK., Taylor RW; Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK robert.taylor@ncl.ac.uk.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2018 Nov; Vol. 10 (11).
DOI: 10.15252/emmm.201809060
Abstrakt: OXA1, the mitochondrial member of the YidC/Alb3/Oxa1 membrane protein insertase family, is required for the assembly of oxidative phosphorylation complexes IV and V in yeast. However, depletion of human OXA1 (OXA1L) was previously reported to impair assembly of complexes I and V only. We report a patient presenting with severe encephalopathy, hypotonia and developmental delay who died at 5 years showing complex IV deficiency in skeletal muscle. Whole exome sequencing identified biallelic OXA1L variants (c.500_507dup, p.(Ser170Glnfs*18) and c.620G>T, p.(Cys207Phe)) that segregated with disease. Patient muscle and fibroblasts showed decreased OXA1L and subunits of complexes IV and V. Crucially, expression of wild-type human OXA1L in patient fibroblasts rescued the complex IV and V defects. Targeted depletion of OXA1L in human cells or Drosophila melanogaster caused defects in the assembly of complexes I, IV and V, consistent with patient data. Immunoprecipitation of OXA1L revealed the enrichment of mtDNA-encoded subunits of complexes I, IV and V. Our data verify the pathogenicity of these OXA1L variants and demonstrate that OXA1L is required for the assembly of multiple respiratory chain complexes.
(© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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