Sequence of the murine Huntington disease gene: evidence for conservation, alternate splicing and polymorphism in a triplet (CCG) repeat [corrected]

Abstract

Huntington disease (HD) is associated with significant expansion of a CAG trinucleotide repeat within a novel gene. However, no clues to the function of this gene were apparent by sequence alignment to other proteins. We have therefore sought to identify the mouse gene (hd) as a first step in the development of an animal model for HD to provide insights into the molecular pathogenesis of this disease. Here, we report the sequencing of cDNA clones spanning 9,992 nucleotides encoding the murine HD homologue (hd), which exhibits 90% peptide sequence identity, including conservation of the CAG and adjacent CCG repeats. In addition, we show that the CCG is polymorphic in the mouse. Sequence analysis provides strong evidence that the first in frame methionine 5' to the CAG repeat, is the translational start site, for both the mouse and human transcript. As in human, the gene appears expressed in the mouse as 2 large transcripts. We observe evidence for alternate splicing of the hd gene in mouse tissues which would predict two protein products differing by 480 amino acid residues with a molecular mass difference of approximately 54 kilodaltons.