دورية أكاديمية
Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease
| العنوان: | Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease |
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| المؤلفون: | Thompson, Kyle, Bianchi, Lucas, Rastelli, Francesca, Piron-Prunier, Florence, Ayciriex, Sophie, Besmond, Claude, Hubert, Laurence, Barth, Magalie, Barbosa, Inês, Deshpande, Charu, Chitre, Manali, Mehta, Sarju, Wever, Eric J.M., Marcorelles, Pascale, Donkervoort, Sandra, Saade, Dimah, Bönnemann, Carsten, Chao, Katherine, Cai, Chunyu, Iannaccone, Susan, Dean, Andrew, Mcfarland, Robert, Vaz, Frédéric, Delahodde, Agnès, Taylor, Robert, Rötig, Agnès |
| المساهمون: | 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 - CNRS Chimie (INC-CNRS)-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 = Universiteit van 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, MD, USA (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, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-15-RAR3-0012,GENOMIT,Mitochondrial Disorders- from a pan-European Registry to medical genetics, toward molecular mechanisms and new therapeutic options(2015), ANR-16-CE16-0025,MitoMotor,Mutations du gène CHCHD10: comment un déficit mitochondrial conduit à la mort des motoneurones(2016) |
| المصدر: | EISSN: 2666-2477 ; Human Genetics and Genomics Advances ; https://hal.science/hal-03675447Test ; Human Genetics and Genomics Advances, 2022, 3 (2), pp.100097. ⟨10.1016/j.xhgg.2022.100097⟩ ; https://www.sciencedirect.com/science/article/pii/S2666247722000136?via%3DihubTest |
| بيانات النشر: | HAL CCSD Cell Press |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | OXPHOS defect, WES/WGS, cardiolipin, mitochondria, mitochondrial disease, mitochondrial phospholipid, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [CHIM]Chemical Sciences |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/35321494; hal-03675447; https://hal.science/hal-03675447Test; https://hal.science/hal-03675447/documentTest; https://hal.science/hal-03675447/file/A1608201-6CCE-4BB0-A991-F48AA09F9EF7.pdf%26pub_id%3D281161Test; PUBMED: 35321494; PUBMEDCENTRAL: PMC8935507 |
| DOI: | 10.1016/j.xhgg.2022.100097 |
| الإتاحة: | https://doi.org/10.1016/j.xhgg.2022.100097Test https://hal.science/hal-03675447Test https://hal.science/hal-03675447/documentTest https://hal.science/hal-03675447/file/A1608201-6CCE-4BB0-A991-F48AA09F9EF7.pdf%26pub_id%3D281161Test |
| حقوق: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.90D0A722 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.xhgg.2022.100097 |
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