Expanding repeats, expanding impact: Somatic instability in myotonic dystrophy type 1 - PubMed
3 hours ago
- #myotonic dystrophy
- #DNA repair
- #somatic instability
- Myotonic dystrophy type 1 (DM1) is caused by a CTG(n) repeat expansion in the DMPK gene.
- The repeat tract becomes unstable when exceeding 35-50 CTG triplets, expanding both intergenerationally and throughout a patient's lifetime.
- Somatic instability is age-dependent, tissue-specific, and expansion-biased, with higher expansion levels correlating with increased disease severity and faster progression.
- In blood, the estimated progenitor allele length (ePAL) predicts age of onset, while in muscle, the modal repeat length is associated with muscle impairment.
- Somatic expansion is driven by DNA mismatch repair (MMR) proteins like MSH3, and variations in MMR genes modify somatic instability and contribute to phenotypic variability.
- The review discusses techniques for quantifying repeat dynamics, findings from patient-derived tissues, and insights from animal and cellular models.