ABSTRACT
The first pathogenic trinucleotide repeat expansions identified, in fragile X mental retardation (FMR) (1) and spinobulbar muscular atrophy (SBMA or Kennedy’s disease) (2), revealed two different pathogenic mechanisms-loss of gene product in recessively inherited FMR, and a pathogenic gain of function in SBMA. In FMR, a non-coding CGG repeat expansion at the 50 end of the FMR1 gene results in a loss of function that is consistent with the recessive inheritance of that disease. SBMA, alternatively, is caused by the expansion of a polyglutamine repeat (encoded by a CAG expansion) within the androgen receptor protein, resulting in a pathogenic protein. The repeat expansions in the two formsofmyotonic dystrophydonot demonstrate either of these pathogenic mechanisms because they are non-coding mutations that result in a highly penetrant dominant disease. Clinical and molecular characterization of the myotonic dystrophies has demonstrated a novel disease mechanism
involving pathogenic effects of repeat expansions that are expressed in RNA but do not encode any protein.
