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Myotonic dystrophy type 1 (DM1) is caused by an unstable expansion of cytosine–thymine–guanine (CTG) repeats in the 3′‐untranslated region of the DMPK gene. The expanded DMPK transcript accumulates in nuclear RNA foci, sequestering RNA‐binding proteins and disrupting splicing regulation via both cis‐ and trans‐acting mechanisms (PMID:10484765). DM1 is inherited in an autosomal dominant pattern with anticipation.
In a multigenerational pedigree, maternal transmission of ∼200 CTG repeats to offspring resulted in further expansion to ∼800, 1500 and 1600 repeats, correlating with earlier onset and increased severity; the two children with ≥1500 repeats exhibited muscle weakness, myotonia and menstrual irregularities including amenorrhea (n = 4 affected relatives) (PMID:8733904). Anticipation and repeat length–phenotype correlation have been confirmed in additional families, with prenatal diagnosis reported in six cases across five families (PMID:2003536).
Large cross‐sectional studies have further defined the genetic spectrum. A Greek national cohort of 434 DM1 patients confirmed autosomal dominant inheritance, multisystem involvement including insulin resistance and cataracts, and mean age at onset of 26.2 ± 15.3 years (PMID:36555146). Somatic mosaicism has been documented: CTG expansions in skeletal muscle DNA were 2– to 13‐fold greater than in leukocytes, indicating tissue‐specific repeat variability (PMID:8285579).
Functionally, expression of mutant DMPK 3′‐UTRs (≥57 CTGs) in C2C12 myoblasts exerts a negative cis effect on protein production and impairs myogenic differentiation; reporter transcript aggregates colocalize in nuclear foci and rescue via Cre‐loxP–mediated deletion of the repeat restores myoblast fusion (PMID:10484765). In vivo, Six5‐deficient mice exhibit cataracts analogous to DM1 patients, implicating DMPK repeat–mediated downregulation of SIX5 and haploinsufficiency in lens pathology (PMID:10802667).
Additional experimental evidence demonstrates mis‐splicing of key transcripts: aberrant inclusion of fetal splice variants in the ryanodine receptor (RyR1) and SERCA1 leads to impaired calcium handling in DM1 muscle (PMID:15972723), and alternative splicing of α-dystrobrevin alters α-syntrophin binding at the dystrophin‐glycoprotein complex (PMID:18299519).
Rare cases of clinically confirmed DM1 without detectable CTG expansions have been reported, underscoring the complexity of diagnosis but not refuting the primary role of DMPK repeat expansions in most patients (PMID:8122879).
Integration of genetic and functional data supports a Strong gene–disease association: autosomal dominant CTG repeat expansion, anticipation, robust segregation across pedigrees, somatic mosaicism, and concordant in vitro and in vivo models. Expanded DMPK repeats act via dual mechanisms—haploinsufficiency and toxic RNA gain‐of‐function—disrupting RNA processing and splicing. Genetic testing for CTG expansion remains the gold standard for diagnosis and enables reproductive counseling, anticipatory management, and tailored multidisciplinary care.
Key Take-home: DMPK CTG repeat expansion analysis informs diagnosis, prognosis and genetic counseling in DM1, guiding clinical management of multisystemic manifestations.
Gene–Disease AssociationStrongAutosomal dominant DMPK CTG repeat expansion with anticipation, documented in multigenerational pedigrees and concordant functional models Genetic EvidenceStrongRepeat expansions identified in >440 DM1 patients across multiple families; somatic mosaicism and prenatal diagnosis confirm genetic mechanism Functional EvidenceStrongIn vitro cis/trans RNA toxicity assays and Six5-deficient mouse model recapitulate key DM1 features |