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Exon skipping caused by splicing mutation in TNNT1 nemaline myopathy


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.

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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).

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Correspondence to Pengfei Lin.

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The authors declare no competing interests.

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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.

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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).

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