Impaired minor tri-snRNP assembly generates differential splicing defects of U12-type introns in lymphoblasts derived from a type I SMA patient

Hum Mol Genet. 2011 Feb 15;20(4):641-8. doi: 10.1093/hmg/ddq508. Epub 2010 Nov 23.

Abstract

The survival of motor neuron (SMN) protein is essential for cytoplasmic assembly of spliceosomal snRNPs. Although the normal proportion of endogenous snRNAs is unevenly altered in spinal muscular atrophy (SMA) tissues, the biogenesis of individual snRNPs is not dramatically affected in SMN-deficient cells. The SMN protein is also required for normal Cajal body (CB) formation, but the functional consequences of CB disruption upon SMN deficiency have not yet been analyzed at the level of macromolecular snRNPs assembly. Here, we show that the SMN protein is required for tri-snRNPs formation and that the level of the minor U4atac/U6atac/U5 tri-snRNPs is dramatically decreased in lymphoblasts derived from a patient suffering from a severe form of SMA. We found also that splicing of some, but not all, minor introns is inhibited in these cells, demonstrating links between SMN deficiency and differential alterations of splicing events mediated by the minor spliceosome. Our results suggest that SMA might result from the inefficient splicing of one or only a few pre-mRNAs carrying minor introns and coding for proteins required for motor neurons function and/or organization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / genetics
  • Coiled Bodies / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Humans
  • Introns / genetics*
  • Lymphocytes / pathology*
  • RNA Splicing / genetics*
  • RNA, Small Nuclear / genetics*
  • Ribonucleoproteins, Small Nuclear* / genetics
  • Ribonucleoproteins, Small Nuclear* / metabolism
  • Spinal Muscular Atrophies of Childhood / genetics
  • Spinal Muscular Atrophies of Childhood / pathology*
  • Spliceosomes / pathology*

Substances

  • RNA, Small Nuclear
  • Ribonucleoproteins, Small Nuclear
  • U12 small nuclear RNA