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Gene Review

DMPK  -  dystrophia myotonica-protein kinase

Homo sapiens

Synonyms: DM, DM-kinase, DM1, DM1 protein kinase, DM1PK, ...
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Disease relevance of DMPK


Psychiatry related information on DMPK


High impact information on DMPK


Chemical compound and disease context of DMPK

  • A 49-year-old man had an 8-year history of persistent, isolated elevation of serum creatine kinase (hyper-CK-emia) without muscle symptoms, and no electromyographic evidence of myotonia; his muscle biopsy showed features reminiscent of myotonic dystrophy (DM), with morphometric findings consistent with those described in DM type 2 (DM2) [14].
  • Compound 22, a potent and selective inhibitor of human cathepsin K exhibited good primary DMPK properties along with promising activity in an in vitro cell-based human osteoclast assay of bone resorption [15].
  • Myotonic dystrophy type 1 (DM1) has been identified as the amplification of a polymorphic (CTG)n repeat in the 3' untranslated region of a gene encoding a serine/threonine kinase (DMPK) [16].
  • Skeletal muscles in distal limbs of Tg26-hDMPK showed myopathy with myotonic discharges coupled with deficit in sarcolemmal chloride channels, required regulators of hyperexcitability [17].
  • To evaluate cerebral metabolism and intergroup differences in closely matched patients with myotonic dystrophy type 2 (DM2, n = 15) and type 1 (DM1, n = 14), we performed (1)H magnetic resonance spectroscopic (MRS) analyses of the occipital and temporoparietal cortical regions as well as of subcortical frontal white matter [18].

Biological context of DMPK


Anatomical context of DMPK

  • Immunohistochemical analysis of skeletal muscle cells shows that MKBP localizes to the cross sections of individual myofibrils at the Z-membrane as well as the neuromuscular junction, where DMPK has been suggested to be concentrated [23].
  • These results suggest that MKBP constitutes a novel stress-responsive system independent of other known sHSPs in muscle cells and that DMPK may be involved in this system by being activated by MKBP [23].
  • The subcellular fractionation of RNA and the separate analysis of DMPK transcripts from each allele reveals that transcripts from expanded DMPK alleles are retained within the nucleus and are absent from the cytoplasm of DM cell lines [24].
  • DMPK protein was detected in the adult retina, conjunctival and ciliary body epithelia and in the smooth muscle of the ciliary body, pupillary sphincter and uveal blood vessels [25].
  • DMPK transcripts were detected in fetal eyes and in adult conjunctival and corneal epithelia, uvea, cellular layers of the retina, optic nerve and in the sclera [25].

Associations of DMPK with chemical compounds


Physical interactions of DMPK

  • CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus [11].
  • In vitro RNA-binding/photocrosslinking studies demonstrate that CUG-BP/hNab50 binds to RNAs containing the Mt-PK 3'-UTR [31].
  • DMPK can also bind Raf-1 kinase, the Ras-activated molecule of the MAP kinase pathway [32].
  • The identification of hnRNP H as a factor capable of binding and possibly modulating nuclear retention of mutant DMPK mRNA may prove to be an important link in our understanding of the molecular mechanisms that lead to DM1 pathogenesis [33].
  • Our data demonstrate that both CUGBP1 and CRT interact with GCU repeats within myotonin protein kinase and with GCN repeats within C/EBPalpha and C/EBPbeta mRNAs [34].

Enzymatic interactions of DMPK


Other interactions of DMPK

  • Methylation of these sites prevents binding of CTCF, indicating that the DM1 locus methylation in congenital DM would disrupt insulator function [11].
  • Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2 [36].
  • We also report that altering the levels of two RNA-BP known to be involved in DM1 pathogenesis, MBNL1 and CUGBP1, modify the (iCUG)480 degenerative phenotypes [37].
  • While CUG-BP1 is the major (CUG)8-binding activity in normal cells, nuclear CUG-BP2 binding activity increases in DM cells [31].
  • Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy [5].

Analytical, diagnostic and therapeutic context of DMPK


  1. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Mahadevan, M.S., Yadava, R.S., Yu, Q., Balijepalli, S., Frenzel-McCardell, C.D., Bourne, T.D., Phillips, L.H. Nat. Genet. (2006) [Pubmed]
  2. Long CTG tracts from the myotonic dystrophy gene induce deletions and rearrangements during recombination at the APRT locus in CHO cells. Meservy, J.L., Sargent, R.G., Iyer, R.R., Chan, F., McKenzie, G.J., Wells, R.D., Wilson, J.H. Mol. Cell. Biol. (2003) [Pubmed]
  3. Myotonic dystrophy: tissue-specific effect of somatic CTG expansions on allele-specific DMAHP/SIX5 expression. Korade-Mirnics, Z., Tarleton, J., Servidei, S., Casey, R.R., Gennarelli, M., Pegoraro, E., Angelini, C., Hoffman, E.P. Hum. Mol. Genet. (1999) [Pubmed]
  4. Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions. Furling, D., Doucet, G., Langlois, M.A., Timchenko, L., Belanger, E., Cossette, L., Puymirat, J. Gene Ther. (2003) [Pubmed]
  5. Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy. Frisch, R., Singleton, K.R., Moses, P.A., Gonzalez, I.L., Carango, P., Marks, H.G., Funanage, V.L. Mol. Genet. Metab. (2001) [Pubmed]
  6. A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24. Le Ber, I., Martinez, M., Campion, D., Laquerrière, A., Bétard, C., Bassez, G., Girard, C., Saugier-Veber, P., Raux, G., Sergeant, N., Magnier, P., Maisonobe, T., Eymard, B., Duyckaerts, C., Delacourte, A., Frebourg, T., Hannequin, D. Brain (2004) [Pubmed]
  7. The pleiotropic expression of the myotonic dystrophy protein kinase gene illustrates the complex relationships between genetic, biological and clinical covariates of male aging. Brisson, D., Houde, G., St-Pierre, J., Vohl, M.C., Mathieu, J., Gaudet, D. The aging male : the official journal of the International Society for the Study of the Aging Male. (2002) [Pubmed]
  8. Cognitive impairment in adult myotonic dystrophies: a longitudinal study. Sansone, V., Gandossini, S., Cotelli, M., Calabria, M., Zanetti, O., Meola, G. Neurol. Sci. (2007) [Pubmed]
  9. A single trinucleotide, 5'AGC3'/5'GCT3', of the triplet-repeat disease genes confers metal ion-induced non-B DNA structure. Kohwi, Y., Wang, H., Kohwi-Shigematsu, T. Nucleic Acids Res. (1993) [Pubmed]
  10. Personality patterns in patients with myotonic dystrophy. Delaporte, C. Arch. Neurol. (1998) [Pubmed]
  11. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Filippova, G.N., Thienes, C.P., Penn, B.H., Cho, D.H., Hu, Y.J., Moore, J.M., Klesert, T.R., Lobanenkov, V.V., Tapscott, S.J. Nat. Genet. (2001) [Pubmed]
  12. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Savkur, R.S., Philips, A.V., Cooper, T.A. Nat. Genet. (2001) [Pubmed]
  13. Ribozyme-mediated trans-splicing of a trinucleotide repeat. Phylactou, L.A., Darrah, C., Wood, M.J. Nat. Genet. (1998) [Pubmed]
  14. Hyper-CK-emia as the sole manifestation of myotonic dystrophy type 2. Merlini, L., Sabatelli, P., Columbaro, M., Bonifazi, E., Pisani, V., Massa, R., Novelli, G. Muscle Nerve (2005) [Pubmed]
  15. Synthesis and evaluation of cis-hexahydropyrrolo[3,2-b]pyrrol-3-one peptidomimetic inhibitors of CAC1 cysteinyl proteinases. Quibell, M., Benn, A., Flinn, N., Monk, T., Ramjee, M., Ray, P., Wang, Y., Watts, J. Bioorg. Med. Chem. (2005) [Pubmed]
  16. Improved method for molecular diagnosis of myotonic dystrophy type 1 (DM1). Erginel-Unaltuna, N., Akbas, F. J. Clin. Lab. Anal. (2004) [Pubmed]
  17. Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy. O'Cochlain, D.F., Perez-Terzic, C., Reyes, S., Kane, G.C., Behfar, A., Hodgson, D.M., Strommen, J.A., Liu, X.K., van den Broek, W., Wansink, D.G., Wieringa, B., Terzic, A. Hum. Mol. Genet. (2004) [Pubmed]
  18. Brain 1H magnetic resonance spectroscopic differences in myotonic dystrophy type 2 and type 1. Vielhaber, S., Jakubiczka, S., Gaul, C., Schoenfeld, M.A., Debska-Vielhaber, G., Zierz, S., Heinze, H.J., Niessen, H.G., Kaufmann, J. Muscle Nerve (2006) [Pubmed]
  19. Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Thornton, C.A., Wymer, J.P., Simmons, Z., McClain, C., Moxley, R.T. Nat. Genet. (1997) [Pubmed]
  20. Fragile-X syndrome and myotonic dystrophy: parallels and paradoxes. Tapscott, S.J., Klesert, T.R., Widrow, R.J., Stöger, R., Laird, C.D. Curr. Opin. Genet. Dev. (1998) [Pubmed]
  21. Characterization of a monoclonal antibody panel shows that the myotonic dystrophy protein kinase, DMPK, is expressed almost exclusively in muscle and heart. Lam, L.T., Pham, Y.C., Nguyen, T.M., Morris, G.E. Hum. Mol. Genet. (2000) [Pubmed]
  22. Changes in myotonic dystrophy protein kinase levels and muscle development in congenital myotonic dystrophy. Furling, D., Lam, l.e. .T., Agbulut, O., Butler-Browne, G.S., Morris, G.E. Am. J. Pathol. (2003) [Pubmed]
  23. MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase. Suzuki, A., Sugiyama, Y., Hayashi, Y., Nyu-i, N., Yoshida, M., Nonaka, I., Ishiura, S., Arahata, K., Ohno, S. J. Cell Biol. (1998) [Pubmed]
  24. Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes. Hamshere, M.G., Newman, E.E., Alwazzan, M., Athwal, B.S., Brook, J.D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  25. Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy. Winchester, C.L., Ferrier, R.K., Sermoni, A., Clark, B.J., Johnson, K.J. Hum. Mol. Genet. (1999) [Pubmed]
  26. Localization of myotonic dystrophy protein kinase in human and rabbit tissues using a new panel of monoclonal antibodies. Pham, Y.C., Man, N., Lam, L.T., Morris, G.E. Hum. Mol. Genet. (1998) [Pubmed]
  27. Myotonic dystrophy protein kinase domains mediate localization, oligomerization, novel catalytic activity, and autoinhibition. Bush, E.W., Helmke, S.M., Birnbaum, R.A., Perryman, M.B. Biochemistry (2000) [Pubmed]
  28. Homodimerization through coiled-coil regions enhances activity of the myotonic dystrophy protein kinase. Zhang, R., Epstein, H.F. FEBS Lett. (2003) [Pubmed]
  29. Myotonic dystrophy protein kinase phosphorylates the myosin phosphatase targeting subunit and inhibits myosin phosphatase activity. Murányi, A., Zhang, R., Liu, F., Hirano, K., Ito, M., Epstein, H.F., Hartshorne, D.J. FEBS Lett. (2001) [Pubmed]
  30. Overexpression of human myotonic dystrophy protein kinase in Schizosaccharomyces pombe induces an abnormal polarized and swollen cell morphology. Sasagawa, N., Kino, Y., Takeshita, Y., Oma, Y., Ishiura, S. J. Biochem. (2003) [Pubmed]
  31. Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Timchenko, L.T., Miller, J.W., Timchenko, N.A., DeVore, D.R., Datar, K.V., Lin, L., Roberts, R., Caskey, C.T., Swanson, M.S. Nucleic Acids Res. (1996) [Pubmed]
  32. Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase. Shimizu, M., Wang, W., Walch, E.T., Dunne, P.W., Epstein, H.F. FEBS Lett. (2000) [Pubmed]
  33. HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. Kim, D.H., Langlois, M.A., Lee, K.B., Riggs, A.D., Puymirat, J., Rossi, J.J. Nucleic Acids Res. (2005) [Pubmed]
  34. Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins. Timchenko, L.T., Iakova, P., Welm, A.L., Cai, Z.J., Timchenko, N.A. Mol. Cell. Biol. (2002) [Pubmed]
  35. Altered phosphorylation and intracellular distribution of a (CUG)n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice. Roberts, R., Timchenko, N.A., Miller, J.W., Reddy, S., Caskey, C.T., Swanson, M.S., Timchenko, L.T. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  36. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Liquori, C.L., Ricker, K., Moseley, M.L., Jacobsen, J.F., Kress, W., Naylor, S.L., Day, J.W., Ranum, L.P. Science (2001) [Pubmed]
  37. MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1. de Haro, M., Al-Ramahi, I., De Gouyon, B., Ukani, L., Rosa, A., Faustino, N.A., Ashizawa, T., Cooper, T.A., Botas, J. Hum. Mol. Genet. (2006) [Pubmed]
  38. PROMM: the expanding phenotype. A family with proximal myopathy, myotonia and deafness. Phillips, M.F., Rogers, M.T., Barnetson, R., Braun, C., Harley, H.G., Myring, J., Stevens, D., Wiles, C.M., Harper, P.S. Neuromuscul. Disord. (1998) [Pubmed]
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