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References OMIM Gene GeneReviews HGMD HGNC
last update : 30-04-2018
Symbol DM1
Location 19q13.32
HGNC id 2923
Name dystrophia myotonica 1
Other name(s) Steinert disease
Corresponding gene DMPK
Other symbol(s) DM
Main clinical features
  • myotonia proximal and distal myopathy, cataract, frontal balding saccadic slowing and cardiopathy, insulin resistance (INSR splicing alteration), with a wide variation and a congenital form (CDM)
  • early involvement of the muscles of the head and neck. Involvement of the extraocular muscles produces ptosis, weakness of eyelid closure, and limitation of extraocular movements, atrophy of masseters, sternocleidomastoids, and the temporalis muscle producing a characteristic haggard appearance
  • characterized by hypotonia, psychomotor retardation, a large number of repeats and a defect in satellite cells probably implicated in the delay in maturation and muscle atrophy in CDM features, with ribonuclear inclusions, key feature of the muscle pathology dues to sequestration of muscleblind proteins
  • DM1 patients are at risk for Fuchs endothelial corneal dystrophy (FECD) and 46% had slit-lamp and specular microscopic findings of FECD ((PMID: 28886202)))
  • Genetic determination autosomal dominant
    Prevalence 1/8000
    Function/system disorder neuromuscular
    Type disease
    Gene product
    Name dystrophia myotonica-protein kinase
    Gene mutationChromosome rearrangementEffectComments
    repeat expansion   abnormal RNA triplet CTG repeat amplification, exerting a cis-dominant effect (haplo insufficiency) compromising DMPK and/or adjacent DMWD and/or SIX5 gene expression and a trans-dominant (gain of function) defect in RNA metabolism, through aberrant recruitment of the EXP proteins to the DMPK transcript (CUG)n expansion
  • associated with induced NKX2-5 expression, the first genetic modifier of DM1-associated RNA toxicity in the heart
  • mutant RNA transcripts of DM1 aberrantly affect the splicing of the same target RNAs, such as chloride channel 1 (CLCN1) and insulin receptor (INSR), resulting in their shared myotonia and insulin resistance
  • DMPK sequesters splicing regulator proteins, in particular muscleblind-like (MBNL1) proteins, which results in incorrect splicing of a number of premRNAs, and this gain-of-function is the direct cause of DM1 (Arambula 2009)
  • the CpG-free expanded CTG repeat appears to maintain a highly polarized pattern of CpG methylation at the DM1 locus, which varies markedly with age and tissues (PMID: 21044947))
  • a direct link between CTG repeat expression and SPEN mislocalization is demonstrated as expression of expanded CTG repeats in normal cells recapitulates cytoplasmic SPEN localization (PMID: 21637295))
  • major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program (PMID: 22884328))
  • aberrant DNA replication and TNR instability are linked in DM1 cells (PMID: 22354993))
  • STAU1 is a splicing regulator and may likely act as a disease modifier in DM1 (Myotonic dystrophy type 1) (PMID: 26824521))
  • DMPK methylation may account for the maternal bias for Congenital DM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator (PMID: 28257691))
  • abundant nuclear RNA foci colocalizing with MBNL1 in endothelial cells of FECD subjects with DM1 (PMID: 28886202))
  • triggered by CTG-repeat expansion in the 3'-untranslated region of the DMPK gene, resulting in a toxic gain of RNA function through sequestration of MBNL1 protein, among others (PMID: 29334465))
  • sequestration of the splicing factor MBNL1 results in aberrant splicing in many genes in DM1 skeletal muscle, whereas MBNL2 plays a leading role in missplicing in the central nervous system (CNS) of patients with DM1 (PMID: 29490267))
  • Genotype/Phenotype correlations
  • CTG repeat length plays a key role in the extent of splicing misregulation and foci formation, thus providing a useful link between the genotype and the molecular cellular phenotype (Botta 2008)