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Genotype-phenotype correlations
Original research
Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation
  1. Yalan Wan1,
  2. Chao Zhou2,
  3. Xingzhi Chang3,
  4. Liwen Wu4,
  5. Yilei Zheng1,
  6. Jiaxi Yu1,
  7. Li Bai1,
  8. Mingyue Luan1,
  9. Meng Yu1,
  10. Qi Wang1,
  11. Wei Zhang1,
  12. Yun Yuan1,
  13. Jianwen Deng1,5,6,
  14. Zhaoxia Wang1,5,6
  1. 1 Department of Neurology, Peking University First Hospital, Beijing, China
  2. 2 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
  3. 3 Department of Pediatrics, Peking University First Hospital, Beijing, China
  4. 4 Department of Neurology, Hunan Children's Hospital, Changsha, China
  5. 5 Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, China
  6. 6 Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing, China
  1. Correspondence to Dr Zhaoxia Wang, Department of Neurology, Peking University First Hospital, Beijing 100034, China; drwangzx{at}163.com; Dr Jianwen Deng, Department of Neurology, Peking University First Hospital, Beijing 100034, China; jianwendeng{at}pkufh.com

Abstract

Background Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy.

Methods A comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the TUBA4A variant.

Results We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

Conclusion Our findings expanded the phenotypic and genetic manifestations of TUBA4A as well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis.

  • Pathology
  • Genetics
  • Neuromuscular Diseases

Data availability statement

Data are available upon reasonable request. The authors confirm that the data supporting the findings of this study are available within the article and its supplementary information.

https://doi.org/10.1136/jmg-2023-109786

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    Data availability statement

    Data are available upon reasonable request. The authors confirm that the data supporting the findings of this study are available within the article and its supplementary information.

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    Footnotes

    • YW and CZ contributed equally.

    • JD and ZW contributed equally.

    • Contributors JD and ZW contributed to the study conception and design. Material preparation and data collection were performed by YW, XC, MY, LW, QW, WZ and YY. Clinical and imaging data analysis was performed by YW, XC, YZ, JD and ZW. Genetic data analysis and bioinformatic analysis were performed by CZ. Figure layout was performed by YW, YZ, JD and ZW. The molecular experiments were performed by YW, LB and ML. The first draft of the manuscript was written by YW, CZ, JD and ZW, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Authors acting as guarantors: ZW and JD.

    • Funding The work was funded by the National Natural Science Foundation of China (82071409, 82171846, U20A20356), National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital, 2023HQ03) and Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital (2023CX05), Capital's Funds for Health Improvement and Research (2022-4-40716) and Beijing Nova Program (20220484017, 20230484403).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.