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.

  • Brief Communication
  • Published:

Exon skipping caused by splicing mutation in TNNT1 nemaline myopathy

Journal of Human Genetics volume 68, pages 97–101 (2023)Cite this article

Subjects

Abstract

The TNNT1 gene encoding the slow skeletal muscle TnT has been identified as a causative gene for nemaline myopathy. TNNT1 nemaline myopathy is mainly characterized by neonatal-onset muscle weakness, pectus carinatum and respiratory insufficiency. Herein, we report on a Chinese girl with TNNT1 nemaline myopathy with mild clinical phenotypes without thoracic deformities or decreased respiratory function. Muscle biopsy showed moderate to marked type 1 fiber atrophy and nemaline rods. Next-generation sequencing identified the compound heterozygous c. 587dupA (p. D196Efs*41) and c. 387+5G>A mutations in the TNNT1 gene according to the transcript NM_003283.4. RNA sequencing revealed complete exon 9 skipping caused by the c. 387+5G>A mutation. Through quantitative PCR, we found that both the truncation c. 587dupA (p. D196Efs*41) and the splicing c. 387+5G>A mutations triggered nonsense-mediated mRNA decay (NMD). Western blotting showed the residual amount of the truncated TNNT1 protein by deletion of exon 9, which may ameliorate the disease to some extent.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2
Fig. 3

References

  1. Wallgren-Pettersson C, Laing NG. Report of the 70th ENMC International Workshop: nemaline myopathy, 11–13 June 1999, Naarden, The Netherlands. Neuromuscul Disord. 2000;10:299–306.

    Article  CAS  Google Scholar 

  2. Laitila J, Wallgren-Pettersson C. Recent advances in nemaline myopathy. Neuromuscul Disord. 2021;31:955–67.

    Article  Google Scholar 

  3. Malfatti E, Bohm J, Lacene E, Beuvin M, Romero NB, Laporte J. A premature stop codon in MYO18B is associated with severe nemaline myopathy with cardiomyopathy. J Neuromuscul Dis. 2015;2:219–27.

    Article  Google Scholar 

  4. Barton PJ, Cullen ME, Townsend PJ, Brand NJ, Mullen AJ, Norman DA, et al. Close physical linkage of human troponin genes: organization, sequence, and expression of the locus encoding cardiac troponin I and slow skeletal troponin T. Genomics. 1999;57:102–9.

    Article  CAS  Google Scholar 

  5. Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, Koch T, et al. A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet. 2000;67:814–21.

    Article  CAS  Google Scholar 

  6. Konersman CG, Freyermuth F, Winder TL, Lawlor MW, Lagier-Tourenne C, Patel SB. Novel autosomal dominant TNNT1 mutation causing nemaline myopathy. Mol Genet Genom Med. 2017;5:678–91.

    Article  CAS  Google Scholar 

  7. D’Amico A, Fattori F, Fiorillo C, Paglietti MG, Testa MBC, Verardo M, et al. ‘Amish Nemaline Myopathy’ in 2 Italian siblings harbouring a novel homozygous mutation in Troponin-I gene. Neuromuscul Disord. 2019;29:766–70.

    Article  Google Scholar 

  8. Petrucci A, Primiano G, Savarese M, Sancricca C, Udd B, Servidei S. Novel TNNT1 mutation and mild nemaline myopathy phenotype in an Italian patient. Neuromuscul Disord. 2021;31:532–8.

    Article  Google Scholar 

  9. Lee S, Eum J, Park S, Ki S, Hwang BJ, Kee Y, et al. TNNT1 myopathy with novel compound heterozygous mutations. Neuromuscul Disord. 2022;32:176–84.

    Article  Google Scholar 

  10. Wang Q, Hu Z, Chang X, Yu M, Xie Z, Lv H, et al. Mutational and clinical spectrum in a cohort of Chinese patients with hereditary nemaline myopathy. Clin Genet. 2020;97:878–89.

    Article  CAS  Google Scholar 

  11. Zhang Y, Yan H, Liu J, Yan H, Ma Y, Wei C, et al. Clinical and genetic features of infancy-onset congenital myopathies from a Chinese paediatric centre. BMC Pediatr. 2022;22:65.

    Article  Google Scholar 

  12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence mutations: 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  Google Scholar 

  13. Zambon AA, Abel F, Linnane B, O’Rourke D, Phadke R, Sewry CA, et al. Troponin-T type 1 (TNNT1)-related nemaline myopathy: unique respiratory phenotype and muscle pathology findings. Neuromuscul Disord. 2022;32:245–54.

    Article  Google Scholar 

  14. van der Pol WL, Leijenaar JF, Spliet WG, Lavrijsen SW, Jansen NJ, Braun KP, et al. Nemaline myopathy caused byTNNT1 mutations in a Dutch pedigree. Mol Genet Genom Med. 2014;2:134–7.

    Article  Google Scholar 

  15. Supek F, Lehner B, Lindeboom RGH. To NMD or not to NMD: nonsense-mediated mRNA decay in cancer and other genetic diseases. Trends Genet. 2021;37:657–68.

    Article  CAS  Google Scholar 

  16. Mondal A, Jin JP. Protein structure-function relationship at work: learning from myopathy mutations of the slow skeletal muscle isoform of troponin T. Front Physiol. 2016;7:449.

    Article  Google Scholar 

Download references

Funding

This study was funded by National Natural Science Foundation of China (Grant No. 82271436 and No. 81901278) and Shandong Provincial Natural Science Foundation (Grant No. ZR2022MH190).

Author information

Authors and Affiliations

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

    Guangyu Wang, Dandan Zhao, Chuanzhu Yan & Pengfei Lin

Authors
  1. Guangyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dandan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chuanzhu Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. 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 and consent to participate

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, G., Zhao, D., Yan, C. et al. Exon skipping caused by splicing mutation in TNNT1 nemaline myopathy. J Hum Genet 68, 97–101 (2023). https://doi.org/10.1038/s10038-022-01096-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-022-01096-z

This article is cited by

Search

Advanced search

Quick links