Somatic Mosaicism of Myotonic Dystrophy
Myotonic dystrophy (DM) is characterized by expanded tracts of short nucleotide sequences:
- (CTG)n trinucleotide repeat, localized to the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19q13.3 for DM1
- (CCTG)n tetranucleotide repeat, localized to the first intron of the zinc finger 9 (Znf9 also known as Cnbp) gene on chromosome 3q21 for DM2
Once repeat counts reach a predictable threshold (>38 repeats for DM1 and >75 repeats in DM2), these sequences become highly unstable. The cellular machinery for DNA replication begins to slip across the expanded region, generating extra copies of the repeated sequence. The length changes caused by this slippage are relatively large, often with gains of 100 repeats or more.
These expansions occur in both somatic and germline tissues. As a result, a single individual may have cells and tissues that differ in repeat count (referred to as somatic mosaicism). Somatic mosaicism likely contributes to the tissue variability and progressive nature of symptoms seen in patients with myotonic dystrophy.
Several features of somatic mosaicism have been observed:
- The changes in repeat counts accumulate over time, so the expanded regions tend to grow through the life of in individuals with DM.
- The rate of change depends primarily on the size of the repeat region, with larger regions being more unstable and showing faster expansion.
- The level of mosaicism varies between tissues (i.e. muscle expansions are typically greater than those seen in circulating lymphocytes). While some tissues retain their original repeat count, gains of 7x over progenitor counts have been observed in other tissues. The rate of change is also tissue-specific.
- The level of mosaicism can vary within a tissue (i.e. expansion is cell-type specific).
Somatic mosaicism confounds the correlation between repeat count and overall phenotypic prognosis. As a result, the use of pre-symptomatic testing in this disorder should be carefully considered. The size of repeat expansions in white blood cells should not be considered predictive of the age of onset and severity of symptoms.
The molecular mechanisms underlying somatic mosaicism are not completely understood. Difficulties exist in obtaining samples from a full range of somatic tissues at multiple time points during a patient’s lifetime. Comprehensive tissue-by-tissue comparisons in humans have not been conducted to date.
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