Regulatory mechanisms of incomplete huntingtin mRNA splicing

Nat Commun. 2018 Sep 27;9(1):3955. doi: 10.1038/s41467-018-06281-3.


Huntington's disease is caused by a CAG repeat expansion in exon 1 of the HTT gene. We have previously shown that exon 1 HTT does not always splice to exon 2 producing a small transcript (HTTexon1) that encodes the highly pathogenic exon 1 HTT protein. The mechanisms by which this incomplete splicing occurs are unknown. Here, we have generated a minigene system that recapitulates the CAG repeat-length dependence of HTTexon1 production, and has allowed us to define the regions of intron 1 necessary for incomplete splicing. We show that manipulation of the expression levels of the splicing factor SRSF6, predicted to bind CAG repeats, modulates this aberrant splicing event and also demonstrate that RNA polymerase II transcription speed regulates the levels of HTTexon1 production. Understanding the mechanisms by which this pathogenic exon 1 HTT is generated may provide the basis for the development of strategies to prevent its production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Exons / genetics
  • Humans
  • Huntingtin Protein / genetics*
  • Mice
  • Models, Biological
  • Models, Genetic
  • Phosphoproteins / metabolism
  • RNA Polymerase II / metabolism
  • RNA Splicing / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Serine-Arginine Splicing Factors / metabolism
  • Transcription, Genetic
  • Trinucleotide Repeat Expansion / genetics


  • Huntingtin Protein
  • Phosphoproteins
  • RNA, Messenger
  • SRSF6 protein, human
  • SRSF6 protein, mouse
  • Serine-Arginine Splicing Factors
  • RNA Polymerase II