https://doi.org/10.4081/ejtm.2026.15606
In-frame exon skipping induced by the c.14510delA variant in RYR1
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Published: 26 August 2026
RNA splicing is a crucial step in eukaryotic gene expression, ensuring the accurate removal of introns and joining of exons to produce mature transcripts. Mutations that alter canonical splice sites or splicing regulatory elements can profoundly affect this process, resulting in aberrant mRNA species and disease. Genetic screening for Malignant Hyperthermia Susceptibility (MHS), resulted in the identified of a frameshift variant in RYR1 (c.14510delA, rs193922877) associated with MHS and core-like structures in skeletal muscle biopsies. The c.14510delA variant causes a frameshift leading to premature truncation of the protein and loss of the C-terminal transmembrane domains. Splice site prediction analysis suggested that this variant could also impact mRNA splicing. Transcript analysis confirmed that the variant induces in-frame skipping of exon 100, resulting in a shorter RYR1 transcript where exon 101 follows exon 99. To our knowledge, this represents the first description of an in-frame exon skipping event in RYR1. Although the functional impact of the resulting channel isoform remains to be fully elucidated, our findings emphasize the importance of mRNA-level investigations in the molecular diagnosis of RYR1-related myopathies.
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1. Wahl MC, Will CL, Lührmann R. (2009) The spliceosome: design principles of a dynamic RNP machine. Cell 2009;136:701–18. DOI: https://doi.org/10.1016/j.cell.2009.02.009
2. Blencowe BJ. Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem Sci 2000;25:106–10. DOI: https://doi.org/10.1016/S0968-0004(00)01549-8
3. Jobbins AM, Reichenbach LF, Lucas CM, Hudson AJ, Burley GA, Eperon IC. The mechanisms of a mammalian splicing enhancer. Nucleic Acids Res 2018;46:2145–58. DOI: https://doi.org/10.1093/nar/gky056
4. Scotti MM, Swanson MS. RNA mis-splicing in disease. Nat Rev Genet 2016;17:19–32. DOI: https://doi.org/10.1038/nrg.2015.3
5. Chu CS, Trapnell BC, Curristin S, et al. Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet 1993;3:151–6. DOI: https://doi.org/10.1038/ng0293-151
6. Muchir A, Bonne G, van der Kooi AJ, et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000;9:1453–9. DOI: https://doi.org/10.1093/hmg/9.9.1453
7. Vasli N, Laugel V, Böhm J, et al. Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype. Eur J Hum Genet 2012;20:701–4. DOI: https://doi.org/10.1038/ejhg.2011.256
8. Torella A, Zanobio M, Zeuli R, et al. The position of nonsense mutations can predict the phenotype severity: A survey on the DMD gene. PLoS One 2020;15:e0237803. DOI: https://doi.org/10.1371/journal.pone.0237803
9. Flucher BE. Skeletal muscle CaV1.1 channelopathies. Pflugers Arch 2020; 472:739–54. DOI: https://doi.org/10.1007/s00424-020-02368-3
10. Singh NN, O'Leary CA, Eich T, et al. Structural Context of a Critical Exon of Spinal Muscular Atrophy Gene. Front Mol Biosci 2022;9:928581. DOI: https://doi.org/10.3389/fmolb.2022.928581
11. Merlini L, Sabatelli P, Cenni V, et al. Myopathic Ehlers-Danlos Syndrome (mEDS) Related to COL12A1: Two Novel Families and Literature Review. Int J Mol Sci 2025;26:5387. DOI: https://doi.org/10.3390/ijms26115387
12. Todd JJ, Sagar V, Lawal TA, et al. Correlation of phenotype with genotype and protein structure in RYR1-related disorders. J Neurol 2018;265:2506–24. DOI: https://doi.org/10.1007/s00415-018-9033-2
13. Rossi D, Catallo MR, Pierantozzi E, Sorrentino V. Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies. J Gen Physiol 2022;154:e202213115. DOI: https://doi.org/10.1085/jgp.202213115
14. Rossi D, Pranzo C, Roccabianca S, et al. Identification of novel potentially causative RYR1 variants in individuals with malignant hyperthermia susceptibility. Neuromuscul Disord 2026;58:106296. DOI: https://doi.org/10.1016/j.nmd.2025.106296
15. Ogasawara M, Nishino I. Update on RYR1-related myopathies. Curr Opin Neurol 2024;37:504–8. DOI: https://doi.org/10.1097/WCO.0000000000001296
16. Rossi D, De Smet P, Lyfenko A, et al. A truncation in the RYR1 gene associated with central core lesions in skeletal muscle fibres. J Med Genet 2007;44:e67. DOI: https://doi.org/10.1136/jmg.2006.043794
17. Monnier N, Ferreiro A, Marty I, et al. A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. Hum Mol Genet 2003;12:1171–78. DOI: https://doi.org/10.1093/hmg/ddg121
18. Zullo A, Perrotta G, D'Angelo R, et al. RYR1 Sequence Variants in Myopathies: Expression and Functional Studies in Two Families. Biomed Res Int 2019;7638946. DOI: https://doi.org/10.1155/2019/7638946
19. Zhao Q, Li X, Liu L, et al. Prenatal diagnosis identifies compound heterozygous variants in RYR1 that causes ultrasound abnormalities in a fetus. BMC Med Genomics 2022;15:202. DOI: https://doi.org/10.1186/s12920-022-01358-x
20. Pierantozzi E, Badin M, Vezzani B, et al. Human pericytes isolated from adipose tissue have better differentiation abilities than their mesenchymal stem cell counterparts. Cell Tissue Res 2015;361:769–78. DOI: https://doi.org/10.1007/s00441-015-2166-z
21. des Georges A, Clarke OB, Zalk R, et al. Structural basis for gating and activation of RyR1. Cell 2016;167:145-57.e17. DOI: https://doi.org/10.1016/j.cell.2016.08.075
22. Samsó M. A guide to the 3D structure of the ryanodine receptor type 1 by cryoEM. Protein Sci 2017;26:52–68. DOI: https://doi.org/10.1002/pro.3052
23. Woll KA, Van Petegem F. Calcium-release channels: structure and function of IP3 receptors and ryanodine receptors. Physiol Rev 2022;102:209–68. DOI: https://doi.org/10.1152/physrev.00033.2020
24. Okubo M, Noguchi S, Hayashi S, et al. Exon skipping induced by nonsense/frameshift mutations in DMD gene results in Becker muscular dystrophy. Hum Genet 2020;139:247–55. DOI: https://doi.org/10.1007/s00439-019-02107-4
25. Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, et al. Predicting Splicing from Primary Sequence with Deep Learning. Cell 2019; 176:535-48.e24. DOI: https://doi.org/10.1016/j.cell.2018.12.015
26. Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 2004;11:377–94. DOI: https://doi.org/10.1089/1066527041410418
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CRediT authorship contribution
Daniela Rossi, conceptualization, investigation, methodology, writing original draft, funding acquisition; Valentina Guardascione, methodology; Matteo Serano, investigation, methodology; Vincenzo Sorrentino, conceptualization, funding acquisition, writing review and editing.
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All data generated or analyzed during this study are included in this published article.
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