“…For instance, an expanded CTG tract could have a direct negative impact on KLHL1 expression through interference with essential KLHL1 promoter elements. This direct mechanism, however, would not easily explain the incomplete penetrance of the SCA8 mutation or the observation that extremely large SCA8 repeat expansions do not appear to cause disease (Juvonen et al, 2000(Juvonen et al, , 2005Vincent et al, 2000;Sobrido et al, 2001;Corral et al, 2005). For this reason, we currently believe that mechanisms that require that the expansion be encoded in a transcript are more likely to be correct, because this provides a plausible explanation for the reduced penetrance associated with the SCA8 expansions (e.g., very large repeats may not be transcribed or spliced efficiently and would therefore not generate pathogenic RNA molecules).…”