A novel, pathogenic dinucleotide deletion in the mitochondrial MT-TY gene causing myasthenia-like features

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• dc.contributor.author Lim, Albert Z.
• dc.contributor.author McMacken, Grace M.
• dc.contributor.author Rastelli, Francesca
• dc.contributor.author Oláhová, Monika
• dc.contributor.author Baty, Karen
• dc.contributor.author Hopton, Sila
• dc.contributor.author Falkous, Gavin
• dc.contributor.author Töpf, Ana
• dc.contributor.author Lochmüller, Hanns
• dc.contributor.author Marini-Bettolo, Chiara
• dc.contributor.author McFarland, Robert
• dc.contributor.author Taylor, Robert W.
• dc.date.accessioned 2020-10-21T06:40:39Z
• dc.date.available 2020-10-21T06:40:39Z
• dc.date.issued 2020
• dc.description.abstract Mitochondrial DNA (mtDNA)-related diseases often pose a diagnostic challenge and require rigorous clinical and laboratory investigation. Pathogenic variants in the mitochondrial tRNA gene MT-TY, which encodes the tRNATyr, are a rare cause of mitochondrial disease. Here we describe a novel m.5860delTA anticodon variant in the MT-TY gene in a patient who initially presented with features akin to a childhood onset myasthenic syndrome. Using histochemical, immunohistochemical and protein studies we demonstrate that this mutation leads to severe biochemical defects of mitochondrial translation, which is reflected in the early onset and progressive phenotype. This case highlights the clinical overlap between mtDNA-related diseases and other neuromuscular disorders, and demonstrates the potential pitfalls in analysis of next generation sequencing results, given whole exome sequencing of a blood DNA sample failed to make a genetics diagnosis. Muscle biopsy remains an important requirement in the diagnosis of mitochondrial disease and in establishing the pathogenicity of novel mtDNA variants.
• dc.description.sponsorship AL, RM and RWT are supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z); RM and RWT also receive support from the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, the Mitochondrial Disease Patient Cohort (UK) (G0800674), Newcastle University Centre for Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council L016354), UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation 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 (http://www.newcastle-mitochondria.com/). GM is supported by the Association of British Neurologists Clinical Research Training Fellowship. Biobanking and Biomedical Resources Research Infrastructure ‐ large prospective cohorts (BBMRI‐LPC) 2016 access call for Whole Exome Sequencing (FP7/2007‐2013), Grant Number: 313010. Data were analyzed using the RD‐Connect Genome‐Phenome Analysis platform developed under FP7/2007‐2013 funded project, Grant Number: 305444.
• dc.format.mimetype application/pdf
• dc.identifier.citation Lim AZ, McMacken G, Rastelli F, Oláhová M, Baty K, Hopton S, Falkous G, Töpf A, Lochmüller H, Marini-Bettolo C, McFarland R, Taylor RW. A novel, pathogenic dinucleotide deletion in the mitochondrial MT-TY gene causing myasthenia-like features. Neuromuscul Disord. 2020; 30(8):661-8. DOI: 10.1016/j.nmd.2020.06.008
• dc.identifier.doi http://dx.doi.org/10.1016/j.nmd.2020.06.008
• dc.identifier.issn 0960-8966
• dc.identifier.uri http://hdl.handle.net/10230/45538
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Neuromuscul Disord. 2020; 30(8):661-8
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/313010
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305444
• dc.rights © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license.(http://creativecommons.org/licenses/by/4.0/)
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Congenital myasthenia syndromes (CMS)
• dc.subject.keyword MTTY gene
• dc.subject.keyword Mitochondrial disease
• dc.subject.keyword Muscle biopsy
• dc.subject.keyword mtDNA tRNA variant
• dc.title A novel, pathogenic dinucleotide deletion in the mitochondrial MT-TY gene causing myasthenia-like features
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion