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Original research
Large TRAPPC11 gene deletions as a cause of muscular dystrophy and their estimated genesis
  1. Johana Kopčilová1,2,
  2. Hana Ptáčková3,
  3. Tereza Kramářová1,
  4. Lenka Fajkusová1,2,
  5. Kamila Réblová1,4,
  6. Jiří Zeman3,
  7. Tomáš Honzík3,
  8. Lucie Zdražilová3,
  9. Josef Zámečník5,
  10. Patrícia Balážová6,
  11. Karin Viestová6,
  12. Miriam Kolníková6,
  13. Hana Hansíková3,
  14. Jana Zídková1
  1. 1 Centre of Molecular Biology and Genetics, Brno University Hospital, Brno, Czech Republic
  2. 2 National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic
  3. 3 Department of Pediatrics and Inherited Metabolic Disorders, Charles University, First Faculty of Medicine, and General University Hospital in Prague, Prague, Czech Republic
  4. 4 Central European Institute of Technology, Masaryk University, Brno, Czech Republic
  5. 5 Department of Pathology and Molecular Medicine, Charles University, Second Faculty of Medicine, and Faculty Hospital Motol, Prague, Czech Republic
  6. 6 Department of Pediatric Neurology, Medical Faculty of Comenius University and Children Faculty Hospital, Bratislava, Slovakia
  1. Correspondence to Dr Jana Zídková, Centre of Molecular Biology and Genetics, Brno University Hospital, Brno 625 00, Czech Republic; zidkova.jana{at}fnbrno.cz; Dr Hana Hansíková, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 12808, Czech Republic; hana.hansikova{at}lf1.cuni.cz

Abstract

Background Transport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and to some extent liver. We present three patients who are compound heterozygotes for a missense variant and a structural variant in the TRAPPC11 gene. TRAPPC11 structural variants have not yet been described in association with a disease. In order to reveal the estimated genesis of identified structural variants, we performed sequencing of individual breakpoint junctions and analysed the extent of homology and the presence of repetitive elements in and around the breakpoints.

Methods Biochemical methods including isoelectric focusing on serum transferrin and apolipoprotein C-III, as well as mitochondrial respiratory chain complex activity measurements, were used. Muscle biopsy samples underwent histochemical analysis. Next-generation sequencing was employed for identifying sequence variants associated with neuromuscular disorders, and Sanger sequencing was used to confirm findings.

Results We suppose that non-homologous end joining is a possible mechanism of deletion origin in two patients and non-allelic homologous recombination in one patient. Analyses of mitochondrial function performed in patients’ skeletal muscles revealed an imbalance of mitochondrial metabolism, which worsens with age and disease progression.

Conclusion Our results contribute to further knowledge in the field of neuromuscular diseases and mutational mechanisms. This knowledge is important for understanding the molecular nature of human diseases and allows us to improve strategies for identifying disease-causing mutations.

  • Neuromuscular Diseases

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jmg-2024-110016

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • JKči and HPčk are joint first authors.

    • JKči and HPčk contributed equally.

    • Correction notice This article has been corrected since it was published online. The postal address of one of the corresponding authors has been added.

    • Contributors JK: molecular genetic diagnostics; detailed analyses of large gene deletions. HP: biochemical analyses; correlation of clinical, biochemical and pathological findings. TK: molecular genetic diagnostics. LF: study design; manuscript writing; the guarantor of study. KR: bioinformatic processing of NGS data. JiZ, TH, PB, KV and MK: evaluation of clinical, biochemical, pathological and other findings. LZ: biochemical analyses. JoZ: pathological analyses. HH: interpretation of biochemical analyses; study design; manuscript writing. JaZ: bioinformatic analyses; interpretation of genetic findings; study design; manuscript writing. All authors had full access to the data in the study, critically revised and approved the final version of the manuscript.

    • Funding This work was supported by Ministry of Health, Czech Republic – conceptual development of research organization (FNBr, 65269705 and VFN, 64165) and Czech Health Research Council (NU21-06-00363 and NU22-07-00474).

    • 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.