Regulation of RNA Processing and RNA-mediated Disease
The expression of unstable microsatellites is associated with a number of neurological and neuromuscular disorders. Many of the dominantly-inherited expansion diseases (e.g. Huntington’sdisease, HD) are caused by trinucleotide repeat expansions in the protein coding region of the corresponding gene. In contrast, the autosomal dominant expansion disease, myotonic dystrophy (DM1), is caused by a CTG expansion in the 3’-untranslated region (3’-UTR) of a protein kinase gene. To explain how a 3’-UTR expansion mutation results in a dominant neuromuscular disorder, we have proposed a toxic RNA model. According to this model, mutant DM1 mRNAs are trapped in the nucleus and sequester (CUG)n-binding proteins that are essential for normal muscle development and function.
We have characterized these sequestered factors as the human muscleblind-like (MBNL) proteins. Current studies are focused on elucidating the normal functions of the MBNL protein family in the regulation of pre-mRNA alternative splicing during postnatal development.
Mouse Models for Neurological and Neuromuscular Disease:
Human muscleblind proteins are homologous to the Drosophila muscleblind (mbl) proteins which are required for terminal differentiation of muscle and photoreceptor tissues in the fly. The human genome contains three muscleblind-like genes-- MBNL, MBNL2, and MBNL3. All three muscleblind genes produce proteins that bind avidly to dsCUG RNA, and current evidence suggests a link between expression of mutant DM1 transcripts and loss of MBNL, MBNL2 and MBNL3 protein function. To elucidate the functions of this gene family during mammalian development, we have isolated and characterized the expression of the mouse muscleblind genes Mbnl1, Mbnl2, and Mbnl3. Alternative pre-mRNA splicing generates multiple muscleblind proteins from each of these genes and these isoforms possess distinct functional properties. We have generated mouse Mbnl1 knockout lines that develop muscle, eye, and RNA splicing changes characteristic of the most prevalent form of adult-onset muscular dystrophy.
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