ReviewRNA pathogenesis of the myotonic dystrophies
Section snippets
Introduction—unstable repeat disorders
A recurring genetic feature of neurodegenerative disorders has been the presence of unstable repeats. Sometimes referred to as microsatellite repeats, or short-tandem repeats, these trinucleotide, tetranucleotide (or longer) elements are repeated a variable number of times, and occur throughout the normal human genome. Each repeat is typically polymorphic in the general population. Repeats can become unstable during DNA replication, resulting in mitotic or meiotic expansions or contractions
History of DM
Almost 100 years ago Steinert [12], and Batten and Gibb [13] independently described the disorder now known as myotonic dystrophy, distinguishing it from Thomsen's previously identified non-dystrophic myotonia [14]. The initial description of the disease focused on skeletal muscle, with myotonia similar to Thomsen's disease, but weakness and atrophy that distinguished the new disorder. Further clinical evaluation revealed the disease to have a complex multisystemic phenotype, with involvement
Identification of DM1 mutation
Prior to identification of the DM1 mutation clinicians had already identified non-Mendelian features in DM1 inheritance, including anticipation (a tendency for the disease to worsen in subsequent generations) and a maternal transmission bias for congenital forms [15], [47]. The genetic cause was identified in 1992 as a (CTG)n repeat in the 3′-untranslated region of the dystrophia myotonica protein kinase gene DMPK [16], [17], [48], [49], [50], making DM1 the first dominantly inherited disease
Mechanisms of RNA toxicity
Efforts to understand how the DM1 CUG expansion expressed at the RNA level could mediate a dominant effect on other genes not localized to the DM1 locus (a so-called ‘trans-dominant’ effect) focused on the identification of RNA-binding proteins that might bind to the CUG repeat motifs. Recent suggestions that ribonuclear inclusions in DM1 and DM2 sequester DNA transcription factors [84] have not yet been confirmed in tissues from affected patients. Direct evidence that RNA containing the repeat
Possibility of DM3
Whether initially described as having PROMM, PDM or DM2, all families identified to date with the complete multisystemic myotonic dystrophy syndrome but without the DM1 mutation on chromosome 19, have been shown to carry the same DM2 mutation. The initial descriptions of several families initially thought to have different clinical disorders are now ascribed to inter-observer differences, and variable presentation of the single disease, DM2 [26]. Linkage disequilibrium and haplotype analysis
Conclusion
The recent clinical and genetic characterization of DM1 and DM2 have now substantiated a third pathogenic mechanism that results from elongated repeat tracts. In addition to the previous recognition that repeat expansions can cause pathogenic loss of gene expression in recessive disorders (e.g. Friedreich's ataxia), or encode novel pathogenic protein products in dominantly inherited disorders (e.g. Huntington's disease), we now realize CUG and CCUG repeat expansions in RNA cause the dominantly
Note added in proof
A recent article demonstrates the location of DM1 ribonuclear inclusions in the central nervous system, and documents abnormal splicing in DM1 brain of the amyloid precursor protein, NMDA NR1 receptors, and tau protein, providing evidence that some CNS features of DM1 result from a trans-dominant alteration of splicing in neurons secondary to the CUG expansion [109].
Acknowledgements
The authors wish to acknowledge the years of productive collaboration with Dr Kenneth Ricker, who died during preparation of this manuscript. His detailed data and his determination to help families with ‘Ricker's disease’ were essential to the thorough clinical and molecular characterization of DM2. We are also grateful to the myotonic dystrophy families who have participated in the research, and who have contributed to the support of the University of Minnesota's Paul and Sheila Wellstone
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