Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Aberrant mRNA processing caused by splicing mutations in TTN-related neuromuscular disorders

Journal of Human Genetics volume 68, pages 777–782 (2023)Cite this article

Subjects

Abstract

Mutations in the TTN gene have been reported to be responsible for a range of neuromuscular disorders, including recessive distal myopathy and congenital myopathy (CM). Only five splicing mutations have been identified to induce aberrant mRNA splicing in TTN-related neuromuscular disorders. In our study, we described detailed clinical characteristics, muscle pathology and genetic analysis of two probands with TTN-related autosomal recessive neuromuscular disorders. Besides, we identified two novel intronic mutations, c.107377+1 G > C in intron 362 and c.19994-2 A > G in intron 68, in the two probands. Through cDNA analysis, we revealed the c.107377+1 G > C mutation induced retention of the entire intron 362, and the c.19994-2 A > G mutation triggered skipping of the first 11 bp of exon 69. Our study broadens the aberrant splicing spectrum of neuromuscular disorders caused by splicing mutations in the TTN gene.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, et al. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res. 2001;89:1065–72.

    Article  PubMed  CAS  Google Scholar 

  2. Kontrogianni-Konstantopoulos A, Ackermann MA, Bowman AL, Yap SV, Bloch RJ. Muscle giants: molecular scaffolds in sarcomerogenesis. Physiol Rev. 2009;89:1217–67.

    Article  PubMed  CAS  Google Scholar 

  3. Linke WA. Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. Cardiovasc Res. 2008;77:637–48.

    PubMed  CAS  Google Scholar 

  4. Puchner EM, Alexandrovich A, Kho AL, Hensen U, Schafer LV, Brandmeier B, et al. Mechanoenzymatics of titin kinase. Proc Natl Acad Sci USA. 2008;105:13385–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Evila A, Vihola A, Sarparanta J, Raheem O, Palmio J, Sandell S, et al. Atypical phenotypes in titinopathies explained by second titin mutations. Ann Neurol. 2014;75:230–40.

    Article  PubMed  Google Scholar 

  6. Evila A, Palmio J, Vihola A, Savarese M, Tasca G, Penttila S, et al. Targeted next-generation sequencing reveals novel TTN mutations causing recessive distal titinopathy. Mol Neurobiol. 2017;54:7212–23.

    Article  PubMed  CAS  Google Scholar 

  7. Rees M, Nikoopour R, Fukuzawa A, Kho AL, Fernandez-Garcia MA, Wraige E, et al. Making sense of missense variants in TTN-related congenital myopathies. Acta Neuropathol. 2021;141:431–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Oates EC, Jones KJ, Donkervoort S, Charlton A, Brammah S, Smith JE 3rd, et al. Congenital titinopathy: comprehensive characterization and pathogenic insights. Ann Neurol. 2018;83:1105–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, DeChene ET, Swanson LC, et al. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology .2013;81:1205–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Harris E, Topf A, Vihola A, Evila A, Barresi R, Hudson J, et al. A ‘second truncation’ in TTN causes early onset recessive muscular dystrophy. Neuromuscul Disord. 2017;27:1009–17.

    Article  PubMed  Google Scholar 

  11. Ge L, Fu X, Zhang W, Wang D, Wang Z, Yuan Y, et al. Recessive mutations in proximal I-band of TTN gene cause severe congenital multi-minicore disease without cardiac involvement. Neuromuscul Disord. 2019;29:350–7.

    Article  PubMed  Google Scholar 

  12. Bryen SJ, Ewans LJ, Pinner J, MacLennan SC, Donkervoort S, Castro D, et al. Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy. Hum Mutat. 2020;41:403–11.

    Article  PubMed  CAS  Google Scholar 

  13. Laddach A, Gautel M, Fraternali F. TITINdb-a computational tool to assess titin’s role as a disease gene. Bioinformatics 2017;33:3482–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Peric S, Glumac JN, Topf A, Savic-Pavicevic D, Phillips L, Johnson K, et al. A novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population. Eur J Hum Genet. 2017;25:572–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Yu M, Zhu Y, Xie Z, Zheng Y, Xiao J, Zhang W, et al. Novel TTN mutations and muscle imaging characteristics in congenital titinopathy. Ann Clin Transl Neurol. 2019;6:1311–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Udd B, Hackman P. Udd Distal Myopathy – Tibial Muscular Dystrophy. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; February 17, 2005.

  18. Tasca G, Udd B. Hereditary myopathy with early respiratory failure (HMERF): Still rare, but common enough. Neuromuscul Disord. 2018;28:268–76.

    Article  PubMed  Google Scholar 

  19. Savarese M, Vihola A, Oates EC, Barresi R, Fiorillo C, Tasca G, et al. Genotype-phenotype correlations in recessive titinopathies. Genet Med. 2020;22:2029–40.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This study was funded by National Natural Science Foundation of China (Grant No. 82271436), Shandong Provincial Natural Science Foundation (Grant No. ZR2022MH190) and Qingdao Science and Technology Benefit People Demonstration Guide Special Project (Grant/Award Number: 22-8-7-smjk-1-nsh).

Author information

Authors and Affiliations

  1. Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China

    Guangyu Wang, Wenjing Wu, Xiaoqing Lv, Chuanzhu Yan & Pengfei Lin

Authors
  1. Guangyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenjing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoqing Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chuanzhu Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pengfei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pengfei Lin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

This study was in compliance with the Declaration of Helsinki and approved by the Ethics Committee of Qilu Hospital of Shandong University. Informed consent was provided by the patient and parents.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, G., Wu, W., Lv, X. et al. Aberrant mRNA processing caused by splicing mutations in TTN-related neuromuscular disorders. J Hum Genet 68, 777–782 (2023). https://doi.org/10.1038/s10038-023-01182-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-023-01182-w

Search

Advanced search

Quick links