SGC target ID

DMPK1A

QUICK FACTS

DMPK1, myotonin-protein kinase, Form I, DM kinase, DM1, DMK, DM protein kinase, MTPK, MDPK, MT-PK, Myotonic dystrophy protein kinase, dystrophia myotonica-protein kinase, dystrophia myotonica 1

Updated

25.Jun.2007

Domain Structure acc. to Pfam

Protein Size

70.36 kDa

#residues

639 aa

Contact info.

Name: Stefan Knapp
E-mail: stefan.knapp@sgc.ox.ac.uk

Entrez Gene

DMPK

cDNA available?

MGC

Gene sequence

L00727

Protein sequence

AAA75236

Biochemical function

Ser/Thr kinase

Biological function

• DMPK is critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction
• It plays a role in muscle differentiation by controlling the rearrangement of the cytoskeleton that takes place during elongation and fusion of myblasts into myotubes

Human mutations

• DM1 is caused by a CTG expansion in the 3' untranslated region of the DMPK gene. The repeat length usually increases in successive generations, but not always
• 1.46% of unrelated patients with cataract, but no evidence or family history of DM1, carry a 'protomutation' in the DMPK gene ranging between 52 and 81 CTG repeats which may represent a source for full expansion mutations
• OMIM: 605377

Mouse models

A large variety of mouse models for DMPK has been created and analysed:

Transgenic mice overexpressing human DMPK:

• produce 6 major alternatively spliced mRNAs which have almost identical cell type-dependent distribution frequencies and expression patterns.

Transgenice mice carrying the CTG expansion in its human DM context:

• Display clinical, histologic, molecular, and electrophysiologic abnormalities in skeletal muscle consistent with those observed in DM patients.
• Like DM patients, these transgenic mice show abnormal tau expression in the brain
• Mice carrying 'humanized' Dmpk allele(s) with either a (CTG)84 or a (CTG)11 repeat inserted at the correct position into the endogenous DM locus:
• Unlike in the human situation, the (CTG)84 repeat in the syntenic mouse environment is relatively stable during intergenerational segregation.
  Somatic tissues show substantial repeat expansions which are progressive upon aging and prominent in kidney, and also in stomach and small intestine, where it is cell-type restricted.
• In the Msh3 -deficient background the somatic repeat instability is completely blocked. Mice with complete absence of Msh3 show decreased frequency of intergenerational expansions and increased frequency of contractions. Decreased formation of expansions, which are more pronounced in maternal transmissions can be observed. Similar for somatic expansions.
• In the Msh6 –deficienct baclground a significant increase in the frequency of somatic expansions is observed. The frequency of expansions decreased only in maternal transmissions, with no obvious changes in somatic instability.

Dmpk transgenic mice (Dmt-D and Dmt-E) containing an expanded CTG/CAG tract on an identical genetic background were generated:

• Sperm from 8-week-old Dmt-D mice have a significantly higher mutation frequency than those of Dmt-E mice of the same age (5.5%), in agreement with pedigree analysis.
• Mutation frequency in sperm of Dmt-D mice increased significantly with age implying that mutations may accumulate with time in spermatogenic stem cells. Similar rates of expansion per spermatogenic cycle in man would yield the large expansions observed in human diseases such as myotonic dystrophy type 1.
• Pedigree data show a significant age-dependent bias toward repeat contraction in female transmissions and a trend toward expansion with age in male transmissions.

Transgenic mice expressing the DMPK 3-prime UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP):

• The expanded (CTG)n tract in the 3-prime UTR of the DMPK gene that causes DM1 results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins, such as MBNL1  in nuclear inclusions.
• Mice overexpressing a normal DMPK 3-prime UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology, and RNA splicing defects in the absence of detectable nuclear inclusions.
• Increased levels of CUG-binding protein (CUGBP) are obsreved in skeletal muscle, as seen in individuals with DM1.
• Effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.

Transgnic mice overexpressing the DMPK 3-prime UTR including either wildtype (11) or expanded (91) CTG repeats:

• Show aberrant and delayed muscle development in fetal transgenic mice.
• Transgenic animals with either expanded or wildtype CTG repeats display muscle atrophy at 3 months of age.
• Primary myoblast cultures from both 11 and 91 repeat mice display reduced fusion potential, but a greater reduction is observed in the 91 repeat cultures.

Aged transgenic mice carrying approximately 25 extra copies of a complete human DMPK gene (Tg26-hDMPK) in cardiac, skeletal, and smooth muscles:

• Show deficient exercise endurance.
• Hearts fromthose mice develop cardiomyopathic remodeling with myocardial hypertrophy, myocyte disarray, and interstitial fibrosis.
• Hypertrophic cardiomyopathy is associated with a propensity for dysrhythmia and characterized by overt intracellular calcium overload promoting nuclear translocation of transcription factors responsible for maladaptive gene reprogramming.
• Skeletal muscles in distal limbs of Tg26-hDMPK mice show myopathy with myotonic discharges coupled with deficit in sarcolemmal chloride channels.
• Fiber degeneration results in sarcomeric disorganization, centralization of nuclei, and tubular aggregation.
• A reduced blood pressure indicats deficient arterial smooth muscle tone.

DMPK knock-out mice (DMPK-/-) display a cardiac phenotype that reproduces many cardiac conduction defects observed in DM patients:

• first-, second-, and third-degree atrioventricular block
• heterozygous DMPK-/- mice develop first-degree heart block, a conduction defect
• cardiac myocytes isolated from DMPK-/- mice show enhanced basal contractility and increased intracellular Ca2+ concentration
• accumulation of hypophosphorylated CUG-BP2 isoform is found in the nuclei of DMPK knockout mice
• hypo-phosphorylated PLN is located in SR vesicles
• Ca2+ uptake in SR is impaired in ventricular homogenates from DMPK-/- mice resulting in enhanced contractility

Other DMPK knockouts, in which  the first 7 exons of  are replaced show:

• mild myopathy
• altered Ca2+ homeostasis
• mild or progressive skeletal myopathy
• reduced skeletal muscle force
• cardiac conduction defects
• abnormal Na+ channel gating
• myoblasts isolated from these mice and in in vitro differentiated Dmpk –/– myotubes altered Ca2+ response has been found
• in skeletal muscle cells isolated from Dmpk –/– and Dmpk +/– mice abnormal Na+ channel opening can be observed

Summary role in disease

• Defects in DMPK are the cause of myotonic dystrophy 1 (DM1) also known as Steinert disease. DM is an autosomal dominant neurodegenerative disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness, and cardiac arrhythmias.
• DM patients show decreased levels of kinase expression inversely related to repeat length. The minimum estimated incidence is 1 in 8'000 live births.
• The 3' untranslated region of this gene contains 5-37 copies of a CTG trinucleotide repeat. Expansion of this unstable motif to 50-5,000 copies causes myotonic dystrophy type I, which increases in severity with increasing repeat element copy number. Repeat expansion is associated with condensation of local chromatin structure that disrupts the expression of genes in this region.
• RNA containing CUG- or CCUG-expanded repeats are transcribed but are retained in the nucleus in foci. Disease pathogenesis results primarily from a gain of function of the expanded RNAs, which alter developmentally regulated alternative splicing as well as pathways of muscle differentiation. The toxic RNA has been implicated in sequestration of splicing regulators and transcription factors thereby causing specific symptoms of the disease.
• Transcription factor leaching from chromatin by mutant RNA provides a potentially unifying pathomechanistic explanation for DM1

Closest
sequence
Matches
(10 or less)

 2.Jul.2007

Closest match in
PDB

 2.Jul.2007

Splice forms and/or domain structure

Ten alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.

ProSite hits

Protein, expression/  Localization

Skeletal muscle at neuromuscular junctions, myotendinous junctions, and terminal cisternae of the sarcoplasmic reticulum (SR)
Intercalated discs in the cardiac muscle
Blood plasma, liver
Cytoplasm, Sarcoplasmatic Reticulum, Gap junctions
Activated in response to G protein second messengers.
Maintained in an inactive conformation by the negative autoregulatory C-terminal coiled-coil region; coiled-coil mediated oligomerization is correlated with enhanced catalytic activity as is proteolytically cleavage near the C-terminus

Gene expression

Most isoforms are expressed in many tissues including heart, skeletal muscle, liver, testis, stomach and brain
Isoform 2 is only found in the heart and skeletal muscle
Isoform 14 is only found in the brain, with high levels in the striatum, cerebellar cortex and pons

Substrates/ cofactors/ inhibitors

Interacting proteins

• Ataxin 1 ubiquitin like interacting protein
• Atrophin 1
• MKBP, Heat shock 27kD protein 2; interaction results in enhanced kinase activity of DMPK and protection  from heat-induced inactivation
• MYPT1, Myosin phosphatase target subunit 1; DMPK phosphorylates MYPT1 at  Thr which results in downregulation of phosphatase activity
• RAF1, kinase; RAF1 phosphorylates and activates DMPK RAC-1
• PLM, Phospholemman, an ion transport regulator; DMPK phosphorylates PLM, which regulates expression of PLM on the membrane
• PLN, Phospholamban, a muscle-specific Sarcoplasmatic Retikulum R Ca2+-ATPase (SERCA2a) inhibitor; DMPK phosphrylates PLN
• CUG-BP, CUG triplet repeat RNA binding protein; interaction results in phosphorylation and regulation of  intracellular localization of CUG-BP which affects the mobility  of CUG-BP/RNA Complex
• voltage-dependent Ca2+ release channel; is substrate for DMPK in vitro
• DHPR dihydropyridine receptor; DMPK can phosphorylate DHPR
• Homomultimers exist which are  mediated by coiled-coil interactions in the tail-proximal domain and occurs independently of alternatively spliced protein segments or myotonic dystrophy protein kinase activity homodimerisation results in enhanced catalytic activity
• DMAP, DNA methyltransferase 1 associated protein 1

Key references

PMID:

1546326
,

8469976
,

14526185
,

14657503
,

16269545
,

16878132
,

16269545
,

16876389
,

15770660

Other comments

The protein encoded by this gene is a serine-threonine kinase that is closely related to other kinases that interact with members of the Rho family of small GTPases.