DMPK

Official Full Name

DM1 protein kinase

Organism

Homo sapiens

GeneID

1760

Background

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. Substrates for this enzyme include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. The 3' untranslated region of this gene contains 5-38 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. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2016]

Synonyms

DM; DM1; DMK; MDPK; DM1PK; MT-PK;

Bio Chemical Class

mRNA target

Protein Sequence

MSAEVRLRRLQQLVLDPGFLGLEPLLDLLLGVHQELGASELAQDKYVADFLQWAEPIVVRLKEVRLQRDDFEILKVIGRGAFSEVAVVKMKQTGQVYAMKIMNKWDMLKRGEVSCFREERDVLVNGDRRWITQLHFAFQDENYLYLVMEYYVGGDLLTLLSKFGERIPAEMARFYLAEIVMAIDSVHRLGYVHRDIKPDNILLDRCGHIRLADFGSCLKLRADGTVRSLVAVGTPDYLSPEILQAVGGGPGTGSYGPECDWWALGVFAYEMFYGQTPFYADSTAETYGKIVHYKEHLSLPLVDEGVPEEARDFIQRLLCPPETRLGRGGAGDFRTHPFFFGLDWDGLRDSVPPFTPDFEGATDTCNFDLVEDGLTAMVSGGGETLSDIREGAPLGVHLPFVGYSYSCMALRDSEVPGPTPMELEAEQLLEPHVQAPSLEPSVSPQDETAEVAVPAAVPAAEAEAEVTLRELQEALEEEVLTRQSLSREMEAIRTDNQNFASQLREAEARNRDLEAHVRQLQERMELLQAEGATAVTGVPSPRATDPPSHLDGPPAVAVGQCPLVGPGPMHRRHLLLPARVPRPGLSEALSLLLFAVVLSRAAALGCIGLVAHAGQLTAVWRRPGAARAP

Open

Disease

Myotonic disorder

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The DMPK gene (Dystrophia Myotonica Protein Kinase Gene) is located on chromosome 19q13.3 and encodes a serine/threonine kinase that primarily interacts with members of the Rho small GTPase family. Among other important intracellular physiological processes, DMPK kinase controls cardiac contractility, balances calcium homeostasis, and preserves muscle shape and function. Phospholemman is one of its substrates; myogenin is the beta subunit of L-type calcium channels. Additionally, DMPK kinase interacts with various transcription factors, signaling molecules, and calcium regulatory proteins, highlighting its significant biological roles in tissues like muscle and heart.

DMPK Gene and Its Relationship with Myotonic Dystrophy (DM)

An autosomal dominant condition influencing several systems, myotonic dystrophy (DM) Two main forms of DM are DM1 and DM2; DM1 is brought on by CTG trinucleotide repeat amplification in the DMPK gene's 3' untranslated region. This growth can cause downregulation or malfunction of the DMPK gene, therefore influencing other organs including muscle performance. With increased CTG repeat expansion, symptoms of DM1 include muscle weakness, atrophy, myotonia, cataracts, cardiac arrhythmias, and diabetes, with degrees growing simultaneously.

As CTG repeats expand, they cause epigenetic changes in the gene that include transcriptional repression and chromatin condensation. This expansion closely correlates with gene dysfunction, resulting in reduced transcription and insufficient DMPK protein production. Particularly in DM1 patients, lower expression levels of DMPK protein are closely linked to clinical symptoms.

Biological Functions of DMPK

The protein encoded by the DMPK gene is a serine/threonine kinase with multiple biological functions. DMPK protein is crucial for maintaining the structure and function of skeletal and cardiac muscles. It regulates the expression of muscle-specific genes and the integrity of the nuclear envelope, participating in muscle cell differentiation and survival. DMPK also inhibits myosin phosphatase activity by phosphorylating PPP1R12A (myosin phosphatase regulating subunit), thus regulating myosin phosphorylation.

In the heart, DMPK protein plays a regulatory role in cardiac contractility and conduction activity by modulating calcium homeostasis. It regulates calcium pumps in muscle cells by phosphorylating PLN (phospholamban), further affecting sarcoplasmic calcium uptake. Additionally, DMPK might influence synaptic plasticity at neuromuscular junctions.

Figure 1 illustrates a hypothetical model of the pathophysiological role of DMPK in DM1, highlighting its kinase activity induced by binding to activated GTPase Rac-1 and Ras-activated Raf-1, with phosphorylation targets linked to various physiological changes observed in DMPK transgenic mice, DMPK-overexpressing systems, and the human disease. Figure 1. Hypothetical model for the pathophysiological role of DMPK in DM1. (Kaliman P, et al., 2008)

Alternative Splicing and DMPK Isoforms

During transcription, the DMPK gene undergoes alternative splicing to form multiple isoforms, differing in structure and function, commonly featuring a kinase domain and a coiled-coil domain. Alternative splicing dictates the presence of certain amino acid sequences and C-terminal variations. For instance, although those with hydrophilic C-termini target the mitochondrial outer membrane, DMPK isoforms with hydrophobic C-termini are usually located in the endoplasmic reticulum.

While cardiac and skeletal muscle long isoforms have longer C-terminals, other DMPK isoforms are linked to particular tissue types, such as a smooth muscle-specific short isoform with a relatively short 2-amino-acid C-terminal sequence. These differences influence their cellular functions and localization, impacting DMPK's multiple biological roles in muscle and other tissues.

Mutations in DMPK Gene and DM Pathogenesis

The pathogenesis of DM1 is primarily linked to the expansion of CTG repeats. This expansion not only affects DMPK gene expression but may alter the three-dimensional structure of chromosomes, impacting adjacent genes. In some models, mutated CTG repeats affect DMPK transcription, leading to nuclear accumulation of transcripts unable to efficiently transport to the cytoplasm, resulting in reduced gene expression. Expanded CTG repeats may also acquire RNA level gain-of-function, binding specific RNA-binding proteins, and causing abnormal RNA splicing.

DMPK gene loss or dysfunction is a major factor in the onset of DM1. Studies show significantly lower DMPK protein levels in DM1 patients compared to normal individuals, correlating with clinical symptoms. Specifically, DMPK protein content decreases by about 50% in skeletal and cardiac muscle tissues, directly relating to muscle weakness and atrophy.

Clinical Manifestations of DM1

DM1 symptoms show significant heterogeneity among patients; generally, the more CTG repeats, the earlier and more severe the symptoms. In early cases, muscle weakness and atrophy typically first appear in distal muscles, progressing to myotonia and multi-system manifestations (e.g., cataracts, arrhythmias, diabetes). Due to the instability of CTG repeats, DM1 also shows "anticipation," where manifestations appear earlier and more severely with each generation.

Non-muscular manifestations of DM1 often precede muscle symptoms, significantly impacting the quality of life, including CNS symptoms like sleep disorders, cognitive decline, and behavioral abnormalities. Cardiac and gastrointestinal symptoms are significant clinical features, requiring multidisciplinary management beyond neuromuscular disease management to address cardiac and GI complications.

References:

Kaliman P, Llagostera E. Myotonic dystrophy protein kinase (DMPK) and its role in the pathogenesis of myotonic dystrophy 1. Cell Signal. 2008 Nov;20(11):1935-41.
Soltanzadeh P. Myotonic Dystrophies: A Genetic Overview. Genes (Basel). 2022 Feb 17;13(2):367.

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