Journal article
Making sense of missense variants in TTN-related congenital myopathies
Acta neuropathologica, Vol.141(3), pp.431-453
2021
DOI: 10.1007/s00401-020-02257-0
PMID: 33449170
Abstract
Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.
Details
- Title: Subtitle
- Making sense of missense variants in TTN-related congenital myopathies
- Creators
- Martin Rees - King's College LondonRoksana Nikoopour - King's College LondonAtsushi Fukuzawa - King's College LondonAy Lin Kho - King‘s College LondonMiguel Fernandez-Garcia - Evelina London Children's HealthcareElizabeth Wraige - Evelina London Children's HospitalIstvan Bodi - University of CambridgeCharu Deshpande - Guy's HospitalÖzkan Özdemir - University of CologneHülya-Sevcan Daimagüler - University of CologneMark Pfuhl - King's College LondonMark Holt - King's College LondonBirgit Brandmeier - King's College LondonSarah Grover - King's College LondonJoël FlussCheryl Longman - Queen Elizabeth University Hospital (Glasgow)Maria Elena Farrugia - Queen Elizabeth University Hospital (Glasgow)Emma Matthews - Queen's UniversityMichael Hanna - University of Iowa, NeurologyAnna Sarkozy - Great Ormond Street HospitalFrancesco Muntoni - Great Ormond Street Hospital for Children [London]Rahul Phadke - Great Ormond Street HospitalRos Quinlivan - Great Ormond Street Hospital for Children [London]Emily Oates - Great Ormond Street Hospital for Children [London]Rolf Schröder - Friedrich-Alexander-Universität Erlangen-NürnbergChristian Thiel - Friedrich-Alexander-Universität Erlangen-NürnbergJens Reimann - University of BonnNicol Voermans - Radboud university [Nijmegen]Corrie Erasmus - Radboud University NijmegenErik-Jan Kamsteeg - University Medical CenterChaminda Konersman - Veterans Health AdministrationCarla GrosmannShane McKee - Belfast City HospitalSandya Tirupathi - Hospital for Sick ChildrenSteven Moore - University of Iowa, PathologyEkkehard Wilichowski - University of GöttingenElke Hobbiebrunken - University of GöttingenGabriele DekomienIsabelle Richard - Approches génétiques intégrées et nouvelles thérapies pour les maladies raresPeter Van den Bergh - Saint-Luc University Hospital [Brussels, Belgium]Cristina Domínguez-González - Hospital Universitario 12 de Octubre [Madrid]Sebahattin Cirak - University of CologneAna Ferreiro - Université Paris CitéHeinz Jungbluth - Guy's HospitalMathias Gautel - King‘s College London
- Resource Type
- Journal article
- Publication Details
- Acta neuropathologica, Vol.141(3), pp.431-453
- DOI
- 10.1007/s00401-020-02257-0
- PMID
- 33449170
- NLM abbreviation
- Acta Neuropathol
- ISSN
- 0001-6322
- eISSN
- 1432-0533
- Publisher
- Springer Verlag
- Grant note
- DOI: 10.13039/501100000274, name: British Heart Foundation, award: RG/15/8/31480; DOI: 10.13039/501100000265, name: Medical Research Council UK, award: MR/R003106/1; DOI: 10.13039/501100000658, name: Myotubular Trust, award: 12KCL01; DOI: 10.13039/100000002, name: National Institutes of Health, award: NS053672; name: Princes Beatrix muscle fund; DOI: 10.13039/501100001659, name: Deutsche Forschungsgemeinschaft, award: Cl 218/1-1; name: Australian NHMRC, award: GNT1090428
- Language
- English
- Date published
- 2021
- Academic Unit
- Neurology; Pathology
- Record Identifier
- 9984186649402771
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