A Mitochondrial tRNA Mutation Causes Axonal CMT in a Large Venezuelan Family
| العنوان: | A Mitochondrial tRNA Mutation Causes Axonal CMT in a Large Venezuelan Family |
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| المؤلفون: | Ying-Hui Fu, Alex J. Fay, Marta Margeta, Claudia Jürgensen, Thomas A. McMahon, Sunita Maharjan, Sitao Yin, Laia Bassaganyas, Ya-Ming Hou, Louis J. Ptáček, Jose Briceño, Yngo Garcia, Mariaelena Garcia |
| المصدر: | Ann Neurol Annals of neurology, vol 88, iss 4 |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, RNA, Mitochondrial, Neurodegenerative, medicine.disease_cause, Muscle hypertrophy, 0302 clinical medicine, RNA, Transfer, Charcot-Marie-Tooth Disease, 80 and over, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics, Aged, 80 and over, Mutation, Middle Aged, Heteroplasmy, Mitochondrial, Pedigree, medicine.anatomical_structure, Neurology, Neurological, Female, Sensory nerve, Adult, Mitochondrial DNA, Adolescent, Clinical Sciences, Biology, Article, 03 medical and health sciences, Young Adult, Rare Diseases, medicine, Humans, Peripheral Neuropathy, Gene, Aged, Neurology & Neurosurgery, Neurosciences, Skeletal muscle, RNA, Venezuela, Transfer, 030104 developmental biology, Neurology (clinical), 030217 neurology & neurosurgery |
| الوصف: | Author(s): Fay, Alexander; Garcia, Yngo; Margeta, Marta; Maharjan, Sunita; Jurgensen, Claudia; Briceno, Jose; Garcia, Mariaelena; Yin, Sitao; Bassaganyas, Laia; McMahon, Thomas; Hou, Ya-Ming; Fu, Ying-Hui; Ptacek, Louis J | Abstract: ObjectiveThe objective of this study was to identify the genetic cause for progressive peripheral nerve disease in a Venezuelan family. Despite the growing list of genes associated with Charcot-Marie-Tooth disease, many patients with axonal forms lack a genetic diagnosis.MethodsA pedigree was constructed, based on family clinical data. Next-generation sequencing of mitochondrial DNA (mtDNA) was performed for 6 affected family members. Muscle biopsies from 4 family members were used for analysis of muscle histology and ultrastructure, mtDNA sequencing, and RNA quantification. Ultrastructural studies were performed on sensory nerve biopsies from 2 affected family members.ResultsElectrodiagnostic testing showed a motor and sensory axonal polyneuropathy. Pedigree analysis revealed inheritance only through the maternal line, consistent with mitochondrial transmission. Sequencing of mtDNA identified a mutation in the mitochondrial tRNAVal (mt-tRNAVal ) gene, m.1661AgG, present at nearly 100% heteroplasmy, which disrupts a Watson-Crick base pair in the T-stem-loop. Muscle biopsies showed chronic denervation/reinnervation changes, whereas biochemical analysis of electron transport chain (ETC) enzyme activities showed reduction in multiple ETC complexes. Northern blots from skeletal muscle total RNA showed severe reduction in abundance of mt-tRNAVal , and mildly increased mt-tRNAPhe , in subjects compared with unrelated age- and sex-matched controls. Nerve biopsies from 2 affected family members demonstrated ultrastructural mitochondrial abnormalities (hyperplasia, hypertrophy, and crystalline arrays) consistent with a mitochondrial neuropathy.ConclusionWe identify a previously unreported cause of Charcot-Marie-Tooth (CMT) disease, a mutation in the mt-tRNAVal , in a Venezuelan family. This work expands the list of CMT-associated genes from protein-coding genes to a mitochondrial tRNA gene. ANN NEUROL 2020;88:830-842. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::34d8d5fe5c3c02ff39610160c557d7d3Test https://europepmc.org/articles/PMC7781299Test/ |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....34d8d5fe5c3c02ff39610160c557d7d3 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |