Journal article

OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect

Kyle Thompson, Nicole Mai, Monika Olahova, Filippo Scialo, Luke E Formosa, David A Stroud, Madeleine Garrett, Nichola Z Lax, Fiona M Robertson, Cristina Jou, Andres Nascimento, Carlos Ortez, Cecilia Jimenez-Mallebrera, Steven A Hardy, Langping He, Garry K Brown, Paula Marttinen, Robert McFarland, Alberto Sanz, Brendan J Battersby Show all

EMBO MOLECULAR MEDICINE | WILEY | Published : 2018

Abstract

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..

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University of Melbourne Researchers

Grants

Awarded by Wellcome Centre for Mitochondrial Research


Awarded by Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK)


Awarded by National Institute of Neurological Disorders and Stroke of the National Institutes of Health


Awarded by Biotechnology and Biological Sciences Research Council


Awarded by National Health & Medical Research Council (NHMRC) of Australia


Awarded by European Regional Development Fund (FEDER)


Funding Acknowledgements

This work is supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK) (G0800674), the Lily Foundation, The Barbour Foundation, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the MRC/EPSRC Molecular Pathology Node, the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (award number R01NS083726 to PEB), the Biotechnology and Biological Sciences Research Council (BB/M023311/1) and the Australian Mitochondria Disease Foundation (AMDF)). MTR and DAS were funded by the National Health & Medical Research Council (NHMRC) of Australia (Grants APP 1125390, 1107094, 1140906) and a Fellowship (1140851) to DAS. CJ-M is funded by the Instituto de Salud Carlos III and the European Regional Development Fund (FEDER) grant CP09/00011. We thank the "Biobanc de l'Hospital Infantil Sant Joan de Deu per a la Investigacio" integrated in the Spanish Biobank Network of ISCIII for patient samples and data procurement.