title: Huntingtin Exists as Multiple Splice Forms in Human Brain.
abstract: BACKGROUND
  A CAG repeat expansion in HTT has been known to cause Huntington's disease for over 20 years. The genomic sequence of the 67 exon HTT is clear but few reports have detailed alternative splicing or alternative transcripts. Most eukaryotic genes with multiple exons show alternative splicing that increases the diversity of the transcriptome and proteome: it would be surprising if a gene with 67 known exons in its two major transcripts did not present some alternative transcripts.
  
  
  OBJECTIVE
  To investigate the presence of alternative transcripts directly in human HTT.
  
  
  METHODS
  An overlapping RT-PCR based approach was used to determine novel HTT splice variants in human brain from HD patients and controls and 3D protein homology modelling employed to investigate their significance on the function of the HTT protein.
  
  
  RESULTS
  Here we show multiple previously unreported novel transcripts of HTT. Of the 22 splice variants found, eight were in-frame with the potential to encode novel HTT protein isoforms. Two splice variants were selected for further study; HTT Δex4,5,6 which results in the skipping of exons 4, 5 and 6 and HTTex41b which includes a novel exon created via partial retention of intron 41. 3D protein homology modelling showed that both splice variants are of potential functional significance leading to the loss of a karyopherin nuclear localisation signal and alterations to sites of posttranslational modification.
  
  
  CONCLUSIONS
  The identification of novel HTT transcripts has implications for HTT protein isoform expression and function. Understanding the functional significance of HTT alternative splicing would be critical to guide the design of potential therapeutics in HD that aim to reduce the toxic HTT transcript or protein product including RNA silencing and correction of mis-splicing in disease.
authors.affiliation: Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mort
authors.affiliation: Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cardiff University, UK.
authors.forename: Francesca A
authors.initials: FA
authors.lastname: Carlisle
authors.affiliation: Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cardiff University, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Waite
authors.affiliation: Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cardiff University, UK.
authors.forename: Lyn
authors.initials: L
authors.lastname: Elliston
authors.affiliation: Cardiff School of Biosciences, Sir Martin Evans Building, Museum Avenue, Cardiff, UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Allen
authors.affiliation: Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cardiff University, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
authors.affiliation: Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cardiff University, UK.
authors.forename: Alis C
authors.initials: AC
authors.lastname: Hughes
mesh_terms: D017398:Alternative Splicing; D001921:Brain / Q000378:metabolism*; D005091:Exons; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
keywords: Huntington’s disease; RNA species; alternative splicing; protein isoforms; structural modelling