Chapter 6 Mechanisms Underlying Noncoding Repeat Expansions

Abstract

Publisher Summary This chapter discusses developments in the field of dominant noncoding microsatellite expansion disorders with a focus on RNA gain-of-function mechanisms. It distinguishes this mechanistic category from noncoding expansions involving loss-of-function disorders, such as fragile X syndrome (FMR1) and Friedreich's ataxia (FA). Both FMR1 and FA are recessive disorders caused by noncoding triplet repeat expansions that result in a loss of protein expression. In contrast to a loss-of-function mechanism, most dominant disorders such as Huntington's disease and a number of spinocerebellar ataxias (SCAs) are caused by gain-of-function mechanisms in which CAG expansions that are translated into polyglutamine tracts modify their corresponding proteins. These initially identified trends fit the paradigm that microsatellite expansions in noncoding regions cause recessive disorders that result in loss-of-function mechanisms and that dominant disorders with expansions in coding regions cause disease through gain-of-function mechanisms. As researchers have identified additional examples of noncoding repeat expansion diseases, this straightforward paradigm has evolved and become more complex. The dominantly inherited myotonic dystrophy type 1 (DM1) is shown to be caused by a CTG expansion in the 3′ untranslated region of the DMPK gene; however, the underlying mechanism remained elusive. Data now demonstrate that an RNA gain-of-function mechanism also plays a role in fragile X–associated tremor ataxia syndrome (FXTAS) and possibly other disorders, including spinocerebellar ataxia type 8 (SCA)8, SCA10, and high-density lipoproteins2.