DMPK (DM1 protein kinase; HGNC:2933, NCBI Gene ID 1760) is a human locus mapped to chromosome band 19q13.32 that encodes myotonic dystrophy protein kinase (629 aa) & 3-prime UTR CUG repeat transcript. DMPK acts in skeletal/cardiac ion channel phosphorylation & toxic RNA spliceopathy in DM1, together with Messenger RNA (mRNA), Small Interfering RNA (siRNA), and Antisense Oligonucleotides (ASOs). Encodes myotonic dystrophy protein kinase; 3-prime UTR CTG repeat expansion causes myotonic dystrophy type 1.
Genomic Organization & Cytogenetic Locus: 15-exon gene on chromosome 19q13.32 encoding a serine/threonine protein kinase related to Rho-associated kinases (ROCK), harboring an unstable polymorphic CTG trinucleotide repeat tract within exon 15 of the 3-prime untranslated region (normally 5 to 34 repeats).
Cellular & Tissue Expression Profile: Expressed predominantly in type I skeletal muscle fibers, cardiac myocytes (especially at intercalated discs and conduction tissue), smooth muscle cells, and central nervous system neurons.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: While the DMPK catalytic domain phosphorylates phospholemman, myosin phosphatase target subunit, and sarcolemmal ion channels to modulate muscle excitability, expanded DMPK mRNA transcripts containing 50 to over 4,000 CUG repeats fold into stable double-stranded hairpins that accumulate in nuclear ribonucleoprotein foci and sequester Muscleblind-like (MBNL1/2/3) splicing factors while hyperactivating CELF1.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: This toxic RNA gain-of-function spliceopathy causes autosomal dominant myotonic dystrophy type 1 (Steinert disease), mis-splicing downstream pre-mRNAs including CLCN1 (causing myotonia), INSR (causing insulin resistance), BIN1 (causing muscle weakness), and SCN5A/TNNT2 (causing cardiac conduction block).
Therapeutic & Clinical Pharmacology: Leading clinical target for antibody-oligonucleotide conjugates (such as delpacibart etedesiran / AOC 1001 siRNA and dyne-101 gapmer ASO), RNase H1-recruiting antisense oligonucleotides, and CRISPR-Cas9/Cas13 excision or degradation of expanded CUG repeat tracts.