Disease relevance of Dmpk

• Thus, since Six5 +/- mice do not exhibit the Na channel gating abnormality of Dmpk deficiency, we conclude that Six5 deficiency does not contribute to the Na channel gating abnormality seen in dystrophia myotonica patients [1].
• Since complete heart block and sudden cardiac death occur in the disease, we tested the hypothesis that cardiac Na channels also exhibit abnormal gating in Dmpk-deficient mice [2].
• As ocular cataracts are a characteristic feature of DM, these results demonstrate that decreased SIX5 transcription is important in the aetiology of DM [3].
• The neuromuscular disease myotonic dystrophy (DM) is caused by microsatellite repeat expansions at two different genomic loci [4].
• Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice [5].

Psychiatry related information on Dmpk

• Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts [3].

High impact information on Dmpk

• A new study shows that normalizing the number of CUG repeat-containing DMPK transcripts in a mouse model of myotonic dystrophy reverses the myotonia and cardiac conduction defects [6].
• To test the role of Six5 loss in DM, we have analysed a strain of mice in which Six5 was deleted [3].
• Previous studies have demonstrated that a dose-dependent loss of Dm15 (the mouse DMPK homologue) in mice produces a partial DM phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders [3].
• Myotonic dystrophy (DM) is one of a growing number of inherited human disorders associated with the expansion of triplet repeat DNA sequences [7].
• Moreover, mitotic instability analysis of different human DM tissues shows length mosaicism between different cell lineages [8].

Chemical compound and disease context of Dmpk

• Myotonic dystrophy is caused by a CTG(n) expansion in the 3'-untranslated region of a serine/threonine protein kinase gene (DMPK), which is flanked by two other genes, DMWD and SIX5 [9].
• Myotonic dystrophy, a progressive autosomal dominant disorder, is associated with an expansion of a CTG repeat tract located in the 3'-untranslated region of a serine/threonine protein kinase, DMPK [10].
• Included are descriptions of the first human C3 genomic DNA clones, their preparation, and their use to map the human C3 gene to chromosome 19 in linkage with the myotonic dystrophy (DM) locus [11].
• To study the role of myotonin in myotonic dystrophy (DM) pathogenesis, we developed a suitable cellular model where myotonin gene expression was modulated by phosphorothioate antisense oligonucleotides in C2 cultured cells [12].

Biological context of Dmpk

• Resting membrane potential was depolarized, and action potential duration was significantly prolonged in Dmpk-deficient muscle [2].
• Myotonic dystrophy (DM) is an autosomal dominant multisystem disorder, caused by expansion of a CTG trinucleotide repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene (DMPK) on chromosome 19q13 [13].
• This pathogenesis model was proposed first for the neuromuscular disease myotonic dystrophy (DM), which is associated with the expansion of structurally related (CTG)(n) and (CCTG)(n) microsatellites in two unrelated genes [14].
• Using FISH we confirmed that the DM-kinase gene is proximal to the ApoE gene on mouse chromosome 7, close to an imprinted segment [15].
• As observed in some of the tissues of DM patients, there is a tendency for repeat length and somatic mosaicism to increase with the age of the mouse [16].

Anatomical context of Dmpk

• We demonstrate that Dmpk mRNA is expressed in a range of adult mouse tissues that show pathology in DM1 including skeletal muscle, heart, smooth muscle, bone, testis, pituitary, brain, eye, skin, thymus and lung [17].
• Significantly, Dmpk mRNA is expressed in the intestinal epithelium, cartilage and liver, which have not been reported to show consistent abnormalities in Dmpk(-/-) mice or in transgenic animals expressing CUG repeats [17].
• Thus in cardiac muscle, Dmpk deficiency results in multiple late reopenings of Na channels similar to those seen in Dmpk-deficient skeletal muscle [2].
• Taken together, our results define an essential function for Dmrt2 in somite development and provide evidence that DM domain genes have been co-opted into other critical developmental pathways distinct from that of sex determination or differentiation [18].
• We studied the regulation of DMPK protein and mRNA expression during myogenesis in rat L6E9 myoblasts, mouse C2C12 myoblasts, and 10T1/2 fibroblasts stably expressing the myogenic transcription factor MyoD (10T1/2-MyoD) [19].

Associations of Dmpk with chemical compounds

• Finally, we show that Ca(2+) uptake in SR is impaired in ventricular homogenates from DMPK(-/-) mice [20].
• Using skeletal muscle from a transgenic mouse model of DM, we show that expression of expanded CUG repeats reduces the transmembrane chloride conductance to levels well below those expected to cause myotonia [21].
• Mutant MtPK cDNA transformants containing 160 CTG repeats showed apoptotic cell death by the exposure to an oxidant, a very low level of methylmercury [22].

Regulatory relationships of Dmpk

• DMPK expression and protein kinase activity were enhanced in IGF-II-differentiated cells [19].
• Expanded CTG repeats in myotonin protein kinase suppresses myogenic differentiation [23].

Other interactions of Dmpk

• Muscle degeneration and myotonia are clinical hallmarks of myotonic dystrophy type 1 (DM1), a multisystemic disorder caused by a CTG repeat expansion in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene [24].
• Dmpk mRNA is not detected in the ovary, pancreas or kidney [17].
• Here, we show that overexpression of Mbnl1 in vivo mediated by transduction of skeletal muscle with a recombinant adeno-associated viral vector rescues disease-associated muscle hyperexcitability, or myotonia, in the HSA(LR) poly(CUG) mouse model for DM [14].
• Targeted disruption of the DM domain containing transcription factor Dmrt2 reveals an essential role in somite patterning [18].
• Following the induction of differentiation of myoblast clones overexpressing the DMK 3'-UTR, the levels of myogenin mRNA were reduced by approximately 4-fold, whereas the steady state levels of mef-2c transcripts were not affected [25].

Analytical, diagnostic and therapeutic context of Dmpk

• In situ hybridization analysis of Dmpk mRNA in adult mouse tissues [17].
• Therefore, to study the effects of the DM mutation in a controlled environment, we have established a cell culture model system using C2C12 mouse myoblasts [26].
• Several polymorphisms within the human DM kinase gene have been identified, and PCR assays to detect two of these are described [27].
• DM pathogenesis studies are presently limited due to the absence of animal models [28].
• We conclude that transplantation of myoblasts from DM patients into SCID mice represents a potential in vivo model for basic studies of this disease [28].

References