Mutation Research
Mutation Research
4 years ago

p.Val19Glyfs*21 and p.Leu228* variants in the survival of motor neuron 1 trigger nonsense-mediated mRNA decay causing the SMN1 PTC+ transcripts degradation

Spinal Muscular Atrophy (SMA) results from loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene. Our previous research showed that 40% of variants were nonsense or frameshift variants and SMN1 mRNA levels in the patients carrying these variants were significantly decreased. Here we selected one rare variant (p.Val19Glyfs*21) and one common variant (p.Leu228*) to explore the degradation mechanism of mutant transcripts. The levels of full-length (FL)-SMN1 transcripts and SMN protein in the cell lines from the patients with these variants were both significantly reduced (p<0.01). Treatment with two translation inhibitors (puromycin and Cycloheximide (CHX)) markedly increased the levels of FL-SMN1 transcripts with premature translation termination codons (PTCs) (p<0.01) and showed time-dependent (10h>5.5h) but not dose-dependent effects. Moreover, the knockdown of UPF1, a key factor in nonsense-mediated mRNA decay (NMD) by lentivirus, led to a 3.08-fold increase (p<0.01) in FL-SMN1 transcript levels in patient fibroblasts. Our research provides evidence that these two PTC-generating variants (p.Val19Glyfs*21 and p.Leu228*) can trigger NMD, causing rapid degradation of SMN1 transcripts thereby resulting in SMN protein deficiency. These two variants are highly pathogenic and are associated with more severe SMA phenotypes. Varying NMD efficiency after treatment with puromycin and CHX in different cell types was also observed.

Publisher URL: www.sciencedirect.com/science

DOI: S002751071730088X

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.