Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease

HGG Advances

卷:3

Pascale Marcorelles¹  Dimah Saade²  Sandra Donkervoort³  Robert W. Taylor⁴  Sarju G. Mehta⁵  Agnès Delahodde⁵  Manali Chitre⁵  Andrew F. Dean⁶  Charu Deshpande⁷  Carsten G. Bönnemann⁸  Frédéric M. Vaz⁹  Robert McFarland⁹  Inês A. Barbosa¹⁰  Lucas Bianchi¹¹  Laurence Hubert¹¹  Claude Besmond¹¹  Eric J.M. Wever¹²  Susan T. Iannaccone¹³  Katherine R. Chao¹³  Chunyu Cai¹³  Magalie Barth¹⁴  Sophie Ayciriex¹⁵  Florence Piron-Prunier¹⁶  Francesca Rastelli¹⁷  Kyle Thompson¹⁷  Agnès Rötig¹⁷ 

[1] Bioinformatics Laboratory, Department of Epidemiology &

[2] Core Facility Metabolomics, Amsterdam UMC, 1105 Amsterdam, the Netherlands;

[3] Data Science, Amsterdam Public Health research institute, 1100 DE Amsterdam UMC, University of Amsterdam, the Netherlands;

[4] Department of Histopathology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK;

[5] Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK;

[6] Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA;

[7] Clinical Genetics Unit, Guys and St. Thomas' NHS Foundation Trust, London SE1 9RT, UK;

[8] Department of Pathology, EA4586 LIEN Université de Brest, CHRU Brest, 29609 Brest, France;

[9] Departments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;

[10] Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK;

[11] INSERM UMR1163, Université Paris Cité, Institut Imagine, 75015 Paris, France;

[12] Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, 1105 AZ Amsterdam, the Netherlands;

[13] National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA;

[14] Service de Génétique, Centre Hospitalier Universitaire Angers, Angers, France;

[15] Univ Lyon, CNRS, Université Claude Bernard Lyon 1, Institut des Sciences Analytiques, UMR 5280, 5 rue de la Doua, 69100 Villeurbanne, France;

[16] Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France;

[17] Wellcome Centre for Mitochondrial Research, Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK;

关键词: cardiolipin;    mitochondria;    mitochondrial disease;    WES/WGS;    OXPHOS defect;    mitochondrial phospholipid;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown