The 'flap' endonuclease gene FEN1 is excluded as a candidate gene implicated in the CAG repeat expansion underlying Huntington disease

At least 12 disorders including Huntington disease (HD) are associated with expansion of a trinucleotide repeat (TNR). Factors contributing to the ris k of expansion of TNRs and the mechanism of expansion have not been elucida ted. Data from Saccharomyces cerevisiae suggest that the flap endonuclease FEN1 plays a role in expansion of repetitive DNA tracts. It has been hypoth esized that insufficiency of FEN1 or a mutant FEN1 might contribute to the occurrence of expansion events of long repetitive DNA tracts after polymera se slippage events during lagging strand synthesis. The expression pattern of FEN1 was determined, and ubiquitous tissue expression, including germ ce lls, suggested that FEN1 has the potential to be involved in HD. Fifteen HD parent/child pairs that demonstrated intergenerational increases in CAG le ngth of greater than 10 repeats were examined for possible mutations or pol ymorphisms within the FEN1 gene that could underlie the saltatory repeat ex pansions seen in these individuals. No alterations were observed compared t o 50 controls, excluding FEN1 as a trans-acting factor underlying TNR expan sion. The identification of a candidate gene(s) in HD or other GAG-expansio n disorders implicated in TNR instability will elucidate the mechanism of e xpansion for this growing family of neurological disorders.