Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease
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
Affiliations
Kyle Thompson
Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
Lucas Bianchi
INSERM UMR1163, Université Paris Cité, Institut Imagine, 75015 Paris, France
Francesca Rastelli
Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
Florence Piron-Prunier
Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France
Sophie Ayciriex
Univ Lyon, CNRS, Université Claude Bernard Lyon 1, Institut des Sciences Analytiques, UMR 5280, 5 rue de la Doua, 69100 Villeurbanne, France
Claude Besmond
INSERM UMR1163, Université Paris Cité, Institut Imagine, 75015 Paris, France
Laurence Hubert
INSERM UMR1163, Université Paris Cité, Institut Imagine, 75015 Paris, France
Magalie Barth
Service de Génétique, Centre Hospitalier Universitaire Angers, Angers, France
Inês A. Barbosa
Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK
Charu Deshpande
Clinical Genetics Unit, Guys and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK
Manali Chitre
Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
Sarju G. Mehta
Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
Eric J.M. Wever
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, the Netherlands; Bioinformatics Laboratory, Department of Epidemiology & Data Science, Amsterdam Public Health research institute, 1100 DE Amsterdam UMC, University of Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, 1105 Amsterdam, the Netherlands
Pascale Marcorelles
Department of Pathology, EA4586 LIEN Université de Brest, CHRU Brest, 29609 Brest, France
Sandra Donkervoort
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Dimah Saade
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Carsten G. Bönnemann
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Katherine R. Chao
Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Chunyu Cai
Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Susan T. Iannaccone
Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Andrew F. Dean
Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK; Department of Histopathology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
Robert McFarland
Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE1 4LP, UK
Frédéric M. Vaz
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, 1105 Amsterdam, the Netherlands; Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Agnès Delahodde
Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France
Robert W. Taylor
Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne NE1 4LP, UK
Summary: 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.
