1. Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease
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Kyle Thompson, Lucas Bianchi, Francesca Rastelli, Florence Piron-Prunier, Sophie Ayciriex, Claude Besmond, Laurence Hubert, Magalie Barth, Inês A. Barbosa, Charu Deshpande, Manali Chitre, Sarju G. Mehta, Eric J.M. Wever, Pascale Marcorelles, Sandra Donkervoort, Dimah Saade, Carsten G. Bönnemann, Katherine R. Chao, Chunyu Cai, Susan T. Iannaccone, Andrew F. Dean, Robert McFarland, Frédéric M. Vaz, Agnès Delahodde, Robert W. Taylor, Agnès Rötig, Newcastle University [Newcastle], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), King‘s College London, Guy's and St Thomas NHS Foundation Trust [London], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), University of Amsterdam [Amsterdam] (UvA), Amsterdam Public Health Research Institute [The Netherlands], Amsterdam UMC - Amsterdam University Medical Center, Laboratoire sur les interactions Epithéliums Neurones (LIEN), Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Texas Southwestern Medical Center [Dallas], Newcastle Upon Tyne Hospitals NHS Foundation Trust, This study was financially supported by the Agence Nationale de la Recherche through the Investissements d'Avenir program ANR-10-IAHU-01 (A.R., L.B., C.B., and L.H.), the E-Rare project GENOMIT (01GM1207, A.R. and L.B.), the French National Agency for Research (ANR-16-CE16-0025-04, A.D. and F.P.-P.), and the 'Association Francaise contre les Myopathies' (AFM -MITOSCREEN, project no. 17122, A.D. and F.P.-P.). We acknowledge the use of bioresources of the Necker Imagine DNA biobank (BB-033-00065). R.M. and R.W.T. are supported by the Wellcome Trust Centre for Mitochondrial Research (203105/Z/16/Z), the Medical Research Council (MRC) International Center for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Mitochondrial Disease Patient Cohort (UK) (G0800674), the UK NIHR Biomedical Research Center for Aging and Age-Related Disease Award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, the Lily Foundation, and the UK NHS Specialist Commissioners, which funds the 'Rare Mitochondrial Disorders of Adults and Children' Diagnostic Service in Newcastle upon Tyne. R.W.T. also receives financial support from the Pathology Society. K.T. and I.A.B. were supported by the Lily Foundation. C.G.B. is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Bussy, Agnès, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, APH - Personalized Medicine, and APH - Methodology
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[CHIM.ANAL] Chemical Sciences/Analytical chemistry ,WES/WGS ,OXPHOS defect ,mitochondria ,mitochondrial disease ,[CHIM.ANAL]Chemical Sciences/Analytical chemistry ,[CHIM] Chemical Sciences ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Molecular Medicine ,[CHIM]Chemical Sciences ,mitochondrial phospholipid ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,cardiolipin ,Genetics (clinical) - Abstract
International audience; Mitochondrial disorders are clinically and genetically heterogeneous, with variants in mitochondrial or nuclear genes leading to varied clinical phenotypes. TAMM41 encodes a mitochondrial protein with cytidine diphosphate-diacylglycerol synthase activity: an essential early step in the biosynthesis of phosphatidylglycerol and cardiolipin. Cardiolipin is a mitochondria-specific phospholipid that is important for many mitochondrial processes. We report three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Whole exome and genome sequencing identified compound heterozygous variants in TAMM41 in each proband. Western blot analysis in fibroblasts showed a mild oxidative phosphorylation (OXPHOS) defect in only one of the three affected individuals. In skeletal muscle samples, however, there was severe loss of subunits of complexes I-IV and a decrease in fully assembled OXPHOS complexes I-V in two subjects as well as decreased TAMM41 protein levels. Similar to the tissue-specific observations on OXPHOS, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. To assess the functional impact of the TAMM41 missense variants, the equivalent mutations were modeled in yeast. All three mutants failed to rescue the growth defect of the Δtam41 strains on non-fermentable (respiratory) medium compared with wild-type TAM41, confirming the pathogenicity of the variants. We establish that TAMM41 is an additional gene involved in mitochondrial phospholipid biosynthesis and modification and that its deficiency results in a mitochondrial disorder, though unlike families with pathogenic AGK (Sengers syndrome) and TAFAZZIN (Barth syndrome) variants, there was no evidence of cardiomyopathy.
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- 2022