Analysis of RNA-Seq datasets reveals enrichment of tissue-specific splice variants for nuclear envelope proteins

Charlotte Capitanchik, Charles Dixon, Selene K Swanson, Laurence Florens, Alastair R W Kerr, Eric C. Schirmer

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Nuclear envelopathies/laminopathies yield tissue-specific pathologies, yet arise from mutation of ubiquitously-expressed genes. One possible explanation of this tissue specificity is that tissue-specific partners become disrupted from larger complexes, but a little investigated alternate hypothesis is that the mutated proteins themselves have tissue-specific splice variants. Here, we analyze RNA-Seq datasets to identify muscle-specific splice variants of nuclear envelope genes that could be relevant to the study of laminopathies, particularly muscular dystrophies, that are not currently annotated in sequence databases. Notably, we found novel isoforms or tissue-specificity of isoforms for: Lap2, linked to cardiomyopathy; Nesprin 2, linked to Emery-Dreifuss muscular dystrophy and Lmo7, a regulator of the emerin gene that is linked to Emery-Dreifuss muscular dystrophy. Interestingly, the muscle-specific exon in Lmo7 is rich in serine phosphorylation motifs, suggesting an important regulatory function. Evidence for muscle-specific splice variants in non-nuclear envelope proteins linked to other muscular dystrophies was also found. Tissue-specific variants were also indicated for several nucleoporins including Nup54, Nup133, Nup153 and Nup358/RanBP2. We confirmed expression of novel Lmo7 and RanBP2 variants with RT-PCR and found that specific knockdown of the Lmo7 variant caused a reduction in myogenic index during mouse C2C12 myogenesis. Global analysis revealed an enrichment of tissue-specific splice variants for nuclear envelope proteins in general compared to the rest of the genome, suggesting that splice variants contribute to regulating its tissue-specific functions.
Original languageEnglish
Pages (from-to)410-430
Number of pages21
Issue number1
Early online date18 Jun 2018
Publication statusE-pub ahead of print - 18 Jun 2018

Keywords / Materials (for Non-textual outputs)

  • tissue-specific
  • nuclear membrane
  • proteomics
  • muscular dystrophy
  • nuclear envelopathies
  • splice variant


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