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FLASH GENE
Symbol DMPK contributors: mct/npt/shn - updated : 01-04-2016
HGNC name dystrophia myotonica-protein kinase
HGNC id 2933
DNA
TYPE functioning gene
STRUCTURE 12.85 kb     15 Exon(s)
10 Kb 5' upstream gene genomic sequence study
motif repetitive sequence   triplet
text structure an unstable (CTG)n repeat in the 3'utr
MAPPING cloned Y linked Y status confirmed
Map cen - D19S908 - D19S219 - DMPK - D19S412 - D19S606 - qter
RNA
TRANSCRIPTS type messenger
text six different splice isoforms that vary in the nature of their C-terminal tails and in the presence or absence of an internal Val-Ser-Gly-Gly-Gly motif
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
15 splicing 2877 74 624 - 2000 10699184
15 splicing 2873 69 625 smooth muscle, specific 2000 10699184
- splicing 4840 69.4 - skeletal muscle, heart, brain, stomach 2000 10699184
  • tail-anchored myotonic dystrophy protein kinase isoform inducing perinuclear clustering of mitochondria, autophagy, and apoptosis
    • - splicing 4840 69 - smooth muscle 2000 10699184
    - splicing 4680 70.3 - skeletal muscle, stomach, brain 2000 10699184
    association to the mitochondrial outer membrane was weakened when the coiled-coil interaction was perturbed
    - splicing 4680 69.6 - skeletal muscle, stomach, brain 2000 10699184
    - splicing 4550 59.8 - smooth muscle 2000 10699184
    - splicing 4550 59.4 - ? 2000 10699184
    15 splicing 2892 - 629 - 2000 10699184
    14 splicing 3261 - 639 - 2000 10699184
    13 - 2722 - 530 - 2000 10699184
    16 - 2933 - 655 - 2000 10699184
    13 - 2510 - 541 - 2000 10699184
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestivesalivary gland   highly
    Nervousbrain   specific
     nervecranial nerve  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularsmooth   
    Muscularstriatumcardiac  
    Muscularstriatumskeletal  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    Text expressed in postmitotic cardiac and skeletal myocytes and developmental signaling centers
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • five distinct domains
  • N terminal stretch leucine-rich
  • a kinase domain S/T type subfamily, with presence, also in LATS2, of two negative pockets in the peptide binding groove provides an explanation for the substrate preference
  • a coiled-coil domain modulating multimerization, substrate binding, kinase activity and subcellular localization characteristics
  • a five AA sequence with unknown function
  • an hydrophobic C terminus
  • an alpha helical domain at various C termini possibly acting as self-association domain or membrane anchor
    • HOMOLOGY
    interspecies ortholog to DMPK, Pan troglodytes
    ortholog to Dmpk, Rattus norvegicus
    ortholog to Dmpk, Mus musculus
    intraspecies homolog to DMR-B15
    Homologene
    FAMILY
  • multidomain protein kinases
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    intracellular,nuclear envelope
    text
  • localised prominently at sites of neuromuscular and myotendinous junctions and rodent skeletal muscles
  • highly enriched in the sarcoplasmic reticulum of cardiac myocytes
  • DMPK A and C proteins both localized to mitochondria
    • basic FUNCTION
  • myotonin serine threonine kinase, modulator of the Ca++ homeostasis in skeletal muscle cell presenting a replication discrepancy between the normal and the mutant allele in cells with the CTG repeat expansion
  • involved in the organization of sarcoplasmic reticulum in skeletal muscle
  • playing a critical role for the modulation of cardiac contractility and the maintenance of proper cardiac conduction activity
  • phosphorylating phospholamban and regulating calcium uptake in cardiomyocyte sarcoplasmic reticulum
  • a kinase with pronounced expression in diverse muscle and neural tissues that are affected in DM1 (Oude 20096)
  • a key role in myocyte differentiation
  • necessary for myogenin expression in differentiating C2C12 myoblasts
  • a critical component of the nuclear envelope
    • CELLULAR PROCESS cell organization/biogenesis
    PHYSIOLOGICAL PROCESS
    text Ca2+ homeostasis in skeletal muscle
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • DMPK-binding protein, MKBP
  • actin cytoskeleton-linked GTPase Rac-1 and Raf-1 kinase
  • phospholamban, PLN
  • Lamin-A/C
  • DDX6 can remodel and release nuclear DMPK messenger ribonucleoprotein foci, leading to normalization of pathogenic alternative splicing events
    • cell & other
    REGULATION
    activated by HSPB2, RAC1, RAF1 suggesting that DMPK plays a role as a nexus between the repetitive pathways af these signals
    induced by intracellular signaling pathways that induce myotonic dystrophy protein kinase expression during myogenesis
    Other enhanced by DMPK-binding protein, MKBP
    ASSOCIATED DISORDERS
    corresponding disease(s) DM1
    Susceptibility
    Variant & Polymorphism repeat associated to spontaneous chromosome loss and colcemid resistance in lymphocytes of DM1
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • mice expressing the CUG expansion in an unrelated mRNA develop myotonia and myopathy, and show abnormal tau expression in the brain
  • overexpression of the DMPK 3'-UTR including either wild-type (11) or expanded (91) CTG repeats results in aberrant and delayed muscle development in fetal transgenic mice, and mice display muscle atrophy at 3 months of age
  • overexpression of DMPK mRNA and protein transgene products in cardiac, skeletal and smooth muscles of transgenic murine line carrying approximately 25 extra copies of a complete hDMPK gene with all exons and an intact promoter region resulted in deficient exercise endurance, hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy
  • PLN is hypo-phosphorylated in SR vesicles from DMPK(-/-) mice compared with wild-type mice
  • mice overexpressing a normal DMPK 3' UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusion
  • inductible DM1 mouse model misregulation of developmentally regulated alternative splicing events, myotonia, characteristic histological abnormalities, and increased CUGBP1 protein levels
  • Overexpression of DMPK induces cell rounding and apoptosis in myocytes
  • Overexpression of DMPK in HeLa cells or C2C12 myoblasts disrupts Lamin-A/C and Lamin-B1 localization and causes nuclear fragmentation, and depletion of DMPK disrupts nuclear envelope lamina