4.7 Article

Premature termination codons in SMN1 leading to spinal muscular atrophy trigger nonsense-mediated mRNA decay

期刊

CLINICA CHIMICA ACTA
卷 530, 期 -, 页码 45-49

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ELSEVIER
DOI: 10.1016/j.cca.2022.02.020

关键词

Mutation; Nonsense-mediated mRNA decay; Premature termination codon; Spinal muscular atrophy; SMN1 gene

资金

  1. Natural Science Foundation of Fujian Province [2021J011271]
  2. Special Clinical Medical Research Program Of 900th Hospital of Joint Logistics Support Force [2019L01]

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This study found that mutations c.683T > A and c.844C > T in the SMN1 gene can trigger spinal muscular atrophy (SMA) and activate the nonsense-mediated mRNA decay (NMD) pathway. Therefore, the role of NMD should be considered when studying the pathogenesis of these mutations.
Background and aims: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by SMN1 gene mutations. About 40% of SMN1 subtle mutations produced premature termination codons (PTC). This study aims to determine the capacity of these PTCs to trigger nonsense-mediated mRNA decay (NMD) pathway.Methods: Three nonsense mutations in SMN1, including c.43C > T, c.683T > A and c.844C > T, were investigated by using a minigene system and in vivo splicing assays. Two strategies were supplied: administration of cycloheximide (NMD inhibitor) and knockdown of UPF1 (a key NMD factor) in the cells carrying different minigenes. Results: The wild-type minigene exclusively produced correctly spliced transcripts (FL-SMN1). Both the 683T > A and 844C > T expressed remarkably lower FL-SMN1 than the wild-type cells. After cycloheximide treatment, the FL-SMN1 levels in both the 683T > A and 844C > T were increased significantly compared with that of untreated cells. UPF1 knockdown in both the mutant 683T > A and 844C > T caused a dramatically augmentation of FL- SMN1 as compared to that in the cells treated with non-specific control siRNAs.Conclusion: Our data provide evidence that c.683T > A and c.844C > T, but not c.43C > T, in SMN1 leading to SMA trigger NMD using a minigene system. Therefore, NMD should be taken into consideration when exploring the pathogenetic mechanisms for these mutations.

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