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Repeats revisited

  • Cathy Holding
Genome Biology20034:spotlight-20031212-03

Published: 12 December 2003


Myotonic DystrophyInfluence Gene ExpressionTriplet RepeatMutant TranscriptFlorida College

The mechanisms by which triplet repeat expansions cause the neurological and muscular defects seen in diseases such as myotonic dystrophy (DM) or fragile X syndrome have been unclear. In the December 12 Science, Rahul N. Kanadia and colleagues at the University of Florida College of Medicine report a hypothesis to explain the occurrence of triplet repeat expansions in different genomic regions - producing two different transcripts, DM1 and DM2 - that result in the same disease. In addition, the authors describe the accumulation of mutant transcripts in muscle nuclei together with proteins in the muscleblind-like (MBNL) family and suggest that normal Mbnl1 binds abnormally to triplet-expanded DM transcripts, interfering with highly specific aspects of pre-mRNA splicing (Science 2003, 302:1978-1980).

Kanadia et al. generated mice homozygous for Mbnl1 deleted for exon 3, previously shown to be required for binding CUG triplet repeats, which developed overt myotonia around 6 weeks of age. Previous observations that skeletal muscle chloride (ClC-1) channel transcripts are aberrantly spliced in transgenic mice exhibiting a DM-like phenotype were examined in the Mbnl1-mutant mice, which also showed abnormal splice variants. Another transcript, fast skeletal muscle troponin, Tnnt2, was also found to be aberrantly spliced.

"These studies confirm a key prediction of the MBNL protein sequestration hypothesis for DM pathogenesis... Although muscleblind-like proteins may influence gene expression at multiple levels, our results raise the possibility that these proteins play a direct role in splice site selection," conclude the authors.


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© BioMed Central Ltd 2003