Book of Abstracts: Albany 2005
Unstable Microsatellites and RNA-Mediated Disease
Microsatellite expansions in the non-coding regions of several genes have been implicated in the pathogenesis of a few inherited neurological and neuromuscular diseases (1). Our studies have focused on the neuromuscular disorder myotonic dystrophy (DM) which is the most prevalent form of adult-onset muscular dystrophy. DM is caused by either a (CTG)n expansion in the 3' untranslated region of the DMPK gene (DM type 1, DM1) or a (CCTG)n expansion in intron 1 of ZNF9 (DM2). To explain how non-coding expansions in two different genes result in a dominantly-inherited adult-onset disease, we have proposed that DM expansions are RNA gain-of function mutations because mutant DMPK and ZNF9 transcripts accumulate in the nucleus and sequester specific double-stranded (ds)RNA-binding factors, the muscleblind-like (MBNL) proteins (2). To test this model, we generated Mbnl1 knockout mice and demonstrated that they develop many of the characteristic features of DM disease, including skeletal muscle myotonia, subcapsular ocular cataracts and cardiomyopathy (3). Current evidence suggests that the MBNL proteins are pre-mRNA splicing factors that regulate alternative splicing during postnatal development and that DM disease results from the retention of neonatal isoforms in the adult (3, 4). Additional examples of RNA-mediated disease may exist and these will be discussed.
References and Footnotes
Rahul N. Kanadia
Department of Molecular Genetics and Microbiology