DIFFERENTIAL 3' POLYADENYLATION OF THE HUNTINGTON DISEASE GENE RESULTS IN 2 MESSENGER-RNA SPECIES WITH VARIABLE TISSUE EXPRESSION

Recently a novel gene containing a CAG trinucleotide repeat that is expanded on HD chromosomes has been identified(1). This gene was shown to detect a single transcript of 10-11 kb by RNA hybridization. We have however, previously identified three cDNAs which are part of the same gene that have been shown to detect two distinct transcripts of 10 kb and one that is significantly larger(2, 3). These different mRNA species could be due to use of alternate transcription start sites, alternate splicing or selection of different polyadenylation sites. We have identified cDNA clones spanning the HD gene including two (HD12 and HD14) that share identical protein coding sequences but differ in size and sequence of their 3' untranslated region. HD14 has 3,360 base pairs of additional sequence distal to the previously published 3' end (1). RNA hybridization has revealed that the larger 13.7 kb fragment is the predominant transcript in human brain. cDNA fragments unique to HD14 detected only the larger transcript. Sequence analysis identified two different putative polyadenylation sequences at position 10,326 and 13,645 of the HD14 cDNA. These findings indicate that the two observed mRNA species originate from a single gene and that differential polyadenylation leads to transcripts of different size. The relative increased abundance of the larger transcript in human brain may provide some insights into the mechanism by which a widely expressed gene may exert tissue specific effects.