Research
Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital
Published

Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Multigenic truncation of the semaphorin-plexin pathway by a germline chromothriptic rearrangement associated with Moebius syndrome

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Aberrant regulation of epigenetic modifiers contributes to the pathogenesis in patients with selenoprotein N-related myopathies

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry)

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Phenotypic Spectrum of α-Dystroglycanopathies Associated With the c.919T>a Variant in the FKRP Gene in Humans and Mice

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults: A Randomized Clinical Trial

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Vacuoles, Often Containing Glycogen, Are a Consistent Finding in Hypokalemic Periodic Paralysis

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Editorial: Remaining diagnostic issues and start of a treatment era for muscle diseases

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Samantha J Bryen
  • Lisa Ewans
  • Jason Pinner
  • Suzanna C MacLennan
  • Sandra Donkervoort
  • Diana Castro
  • Ana Töpf
  • Gina O'Grady
  • Beryl Cummings
  • Katherine R Chao
  • Ben Weisburd
  • Laurent Francioli
  • Fathin Faiz
  • Adam M Bournazos
  • Ying Hu
  • Denise M Malicki
  • Helen Doyle
  • Nanna Witting
  • John Vissing
  • Kristl G Claeys
  • Kathryn Urankar
  • Ana Beleza-Meireles
  • Julia Baptista
  • Sian Ellard
  • Anirban Majumdar
  • Volker Straub
  • Carsten Bonnemann
  • Daniel G MacArthur
  • Mark R Davis
  • Sandra T Cooper
View graph of relations

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥ 66%). Further, RNA-sequencing of five fetal muscle samples confirms 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Importantly, contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalHuman Mutation
Volume41
Issue number2
Pages (from-to)403-411
ISSN1059-7794
DOIs
Publication statusPublished - 1 Feb 2020

Bibliographical note

© 2019 Wiley Periodicals, Inc.

    Research areas

  • alternative splicing, arthrogryposis, congenital titinopathies, intronic splice variant, TTN metatranscript-only

ID: 58451214