Dynamic mutations on the move in Banff

Abstract

Because a universal pathogenic pathway for diseases that have a common mutation type and, often, a common pathology has thus far been elusive, most investigators classify the diseases associated with unstable repeats according to the nature of the mutation mechanism (loss of function, protein gain of function, RNA gain of function). The emerging (and somewhat surprising) role of RNA as the pathogenic agent in DM1, DM2, SCA8 and FXTAS allows the inevitable speculation that RNA accumulation and coalescence of abnormal RNA-protein complexes could be involved in other dominant dynamic mutation disorders not associated with polyglutamine expansion. Mechanistically similar, but uniquely protein-based, mechanisms may have a key role in diseases associated with polyglutamines, although involvement of RNA has not been completely excluded for all disorders in this category. Certainly, a role for RNA toxicity in the polyglutamine-associated disease SCA6 and perhaps even in the Huntington disease-like-2 repeat disorder seems plausible. As for the basis of repeat instability, the interplay between cis elements and trans-acting factors is still shrouded in mystery, and so there is much work to be done. One thing can be concluded with certainty, however. In a field that has been yielding surprises for more than a decade, there are many more in store for the participants of the next International Conference on Unstable Microsatellites and Human Disease, to be held in 2006. The place at which the investigators will then aggregate is yet to be localized, so stay tuned!