Myotonic Dystrophy Molecular Basis of Disease

Myotonic dystrophy (DM) is the most common inherited form of muscular dystrophy affecting adults, having an incidence of approximately 1 in 8,000 individuals. DM is an autosomal dominant, multisystem disorder characterized by progressive muscle weakness and myotonia. The diagnosis can be problematic because of the wide range and severity of symptoms. Often, affected individuals have children before they are diagnosed. A severe congenital form of DM results in mental retardation, respiratory distress, hypotonia, and in many cases death due to respiratory complications shortly after birth. The congenital form is seen in the offspring of women who are themselves mildly affected.17 The clinical genetic phenomenon of anticipation occurs in DM. Anticipation denotes progressively earlier appearance of a disease in successive generations, generally with increasing severity.

The DM mutation has been characterized as an unstable trinucleotide repeat present on chromosome 19q13.3.18-20 A polymorphic CTG repeat ranges in size from 5 to approximately 30 repeats in the normal population. Mildly affected patients have 50 to 80 repeats, whereas more severely affected individuals have more than 1,000 repeats. The number of repeats varies between affected sibs and increases through generations in parallel with an increasing severity of the disease. Expansion of the CTG repeat between generations accounts for the clinical genetic anticipation phenomenon.

The CTG repeat is located within the 3' untranslated region of the DMPK gene that encodes a protein kinase, named myotonin protein kinase. Since protein kinases are involved in signal transduction pathways in all cells in the body, a defective protein kinase may explain how a single gene defect could result in the diverse symptoms characteristic of DM. However, since the repeat is not in the protein coding region of DMPK, the molecular mechanism by which the mutation exerts its dominant expression is difficult to explain. A study using quantitative reverse transcription-PCR (RT-PCR) and a radioimmunoassay demonstrated that decreased levels of mRNA and protein expression are associated with the adult form of DM,21 suggesting that the dominant nature of DM is likely the result of a dosage-dependent mechanism. However, in another report, expression studies on samples from congenital DM cases demonstrated marked increases in the steady-state levels of the DMPK mRNA.22 In contrast to a reduction of myotonin kinase, the authors proposed that the effect of the mutation would be a nonregulated hyperphosphoryla-tion of kinase substrate by high levels of myotonin kinase.

Another possible disease mechanism is that the repeat expansion affects the expression of other genes in the region. Since the CTG expansion is located in the 3'-untranslated region of the gene, downstream gene expression, like that of DM locus-associated homeodomain protein (DMAHP) may be downregulated. Finally, other studies have suggested a novel type of pathogenic mechanism in which the DMPK mRNA with long CUG repeats, and not the protein, results in the pathology. Novel RNA-binding proteins that specifically bind to CUG repeats may be depleted by excessive CUG repeats, or abnormalities in these proteins may disrupt the metabolism of DMPK mRNA and other transcripts. Further studies are necessary to define precisely the mechanism by which the repeat expansions cause the DM disease symptoms.

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