Myotonin-protein kinase (MT-PK) also known as myotonic dystrophy protein kinase (MDPK) or dystrophia myotonica protein kinase (DMPK) is an enzyme that in humans is encoded by the DMPK gene. (wikipedia.org)
Dystrophia myotonica protein kinase (DMPK) is a serine/threonine kinase composed of a kinase domain and a coiled-coil domain involved in the multimerization. (wikipedia.org)
A CTG repeat element normally resides in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, but when expanded it is the genetic lesion of myotonic dystrophy type 1 (DM1), a hereditary neuromuscular disease. (bvsalud.org)
Enzyme1
The crystal structure of the kinase domain of DMPK bound to the inhibitor bisindolylmaleimide VIII (BIM-8) revealed a dimeric enzyme associated by a conserved dimerization domain. (wikipedia.org)
Attachment2
The RSV Glycoprotein (G) mediates attachment of the virus to the cell membrane, which facilitates interaction of the RSV Fusion (F) protein with nucleolin, thereby triggering fusion of the viral and cellular membranes. (bvsalud.org)
Mediates attachment of the chromosome to the meiotic or mitotic spindle . (amboss.com)
Antibodies2
Data obtained by using antibodies that detect specific isoforms of DMPK indicate that the most abundant isoform of DMPK is an 80-kDa protein expressed almost exclusively in smooth, skeletal, and cardiac muscles. (wikipedia.org)
Central nervous system (CNS) gene transfer by vectors like adeno-associated virus (AAV) overcome this barrier by allowing the bodies' own cells to produce the therapeutic protein, but previous studies using this method to target amyloid-ß have shown success only with truncated single chain antibodies (Abs) lacking an Fc domain. (bvsalud.org)
Genetic1
Genetic disorders result from new or inherited gene mutations . (amboss.com)
Expression3
Repeat expansion is associated with condensation of local chromatin structure that disrupts the expression of genes in this region. (wikipedia.org)
AAV-mediated expression of this scFv-IgG reduced cortical and hippocampal plaque load in a transgenic mouse model of progressive ß-amyloid plaque accumulation. (bvsalud.org)
Epigenetic regulation of gene expression encompasses mechanisms that allow regulating the expression of the genes without modification of the DNA sequence. (amboss.com)
Protein3
The dmpk gene product is a Ser/Thr protein kinase homologous to the MRCK p21-activated kinases and Rho kinase family. (wikipedia.org)
In this model, transient activation of kinase activity would occur in response to G protein second messengers, while longterm activation of DMPK could be mediated by a membrane associated protease that cleaves DMPK-1 to release cytosolic DMPK-2 in a persistently activated form. (wikipedia.org)
Wucherpfennig, K.W. and Hafler, D.A. (1995) A review of T-cell receptors in multiple sclerosis: Clonal expansion and persistence of human T-cells specific for an immunodominant myelin basic protein peptide. (scirp.org)
Copies3
The 3' untranslated region of this gene contains 5-37 copies of a CTG trinucleotide repeat. (wikipedia.org)
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. (wikipedia.org)
In a population of 250 individuals , there will be a total of 500 gene copies (all individuals carry two alleles of a gene ). (amboss.com)
Disorders2
Next-generation sequencing of the whole exome is useful for testing for multiple candidate genes simultaneously or for discovering new, rare disorders. (medlink.com)
Whole exome sequencing is not suitable for detecting polynucleotide repeat disorders or large insertion/deletions. (medlink.com)
Sequence1
Herein, we demonstrate molecular and physiological amelioration of the toxic effects of mutant RNA in the HSA(LR) mouse model of DM1 by systemic administration of peptide-linked morpholino (PPMO) antisense oligonucleotides bearing a CAG repeat sequence. (bvsalud.org)
Region1
The Fc region mediates effector function and enhances antigen clearance from the brain by neonatal Fc receptor (FcRn)-mediated reverse transcytosis and is therefore desirable to include for such treatments. (bvsalud.org)
Cells2
The different C termini of DMPK that arise from alternative splicing determine its localization to the endoplasmic reticulum, mitochondria, or cytosol in transfected COS-1 cells. (wikipedia.org)
Komatsu, T., Moriya, N. and Shiohara, T. (1996) T cell receptor (TCR) repertoire and function of human epidermal T cells: Restricted TCR V alpha-V beta genes are utilized by T cells residing in the lesional epidermis in fixed drug eruption. (scirp.org)
Domain2
Although DMPK lacks obvious binding sites for known G, DMPK-1 oligomers exhibit low basal catalytic activity due to the presence of the C-terminal autoinhibitory domain (AI). (wikipedia.org)
Here, we show that single chain Abs fused to an Fc domain retaining FcRn binding, but lacking Fc gamma receptor (FcγR) binding, termed a silent scFv-IgG, can be expressed and released into the CNS following gene transfer with AAV. (bvsalud.org)
Human1
Human genetics is the study of the human genome and the transmission of genes from one generation to the next. (amboss.com)
Leads2
As the DMPK repeat is replicated, the hairpin loop that is formed leads to repeat expansion (a) or contractions (b). (wikipedia.org)
Expansions of CUG trinucleotide sequences in RNA transcripts provide the basis for toxic RNA gain-of-function that leads to detrimental changes in RNA metabolism. (bvsalud.org)
Chromosome 192
Its molecular basis is an expansion of a CTG repeat in the 3′ untranslated region (UTR) of the DMPK gene on chromosome 19. (bmj.com)
MMD results from a trinucleotide repeat (CTG) in the DMPK gene region on chromosome 19. (medicalhomeportal.org)
Pathogenic4
However, pathogenic loci bear expanded alleles of up to several hundred or even thousand repeats in severe cases. (bmj.com)
As with many other tandemly repeated microsatellite sequences, pathogenic TNRs are highly unstable in both the somatic and germ cell lineage, leading to expansions and contractions in the length of the repeats in successive cell or individual generations. (bmj.com)
The pathogenic DMPK transcript containing the CUG expansion is retained in ribonuclear foci as part of a complex with RNA-binding proteins such as muscleblind-like 1 (MBNL1), resulting in aberrant splicing of numerous RNA transcripts and consequent physiological abnormalities including myotonia. (bvsalud.org)
Pathogenic alleles may expand in length during gametogenesis, resulting in the transmission of longer trinucleotide repeat alleles that may be associated with earlier onset and more severe disease than that observed in the parent. (nih.gov)
Myotonic5
However, an in vivo demonstration of the phosphorylation of these substrates by DMPK remains to be established, and a link between these substrates and the clinical manifestations of myotonic dystrophy (DM) is unclear. (wikipedia.org)
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. (wikipedia.org)
The poster presentation, titled "AAV9 Mediated Delivery of RNA Targeting Systems Corrects Molecular and Functional Defects in Myotonic Dystrophy Type 1," is available on the Events & Presentations section of the company's website at https://locanabio.com/wp-content/uploads/2021/11/Muscle_Society.pdf . (locanabio.com)
The mutation is termed a repeat expansion mutation because it is characterized by long repeats of the trinucleotide CUG in the DMPK pre-mRNA. (expansionrx.com)
31 Therefore, we have hypothesised that mutagenic stress could result in an induction of instability of unexpanded TNR sequences, leading to an increase in the frequency of spontaneously occurring contractions/expansions in repeat number. (bmj.com)
To test this hypothesis, we analysed normal length TNR sequences at a single repeat resolution by radioactive PCR and denaturating polyacrylamide gels, using DNA from multiple single cell clones expanded in the presence or absence of mitomycin-C (MMC), a mutagenic agent able to induce interstrand DNA cross links, strand breaks, and replication blockage. (bmj.com)
DM1 patients carry toxic RNA repeat sequences lurking in an intron of the DMPK pre-mRNA. (expansionrx.com)
Expansions of CUG trinucleotide sequences in RNA transcripts provide the basis for toxic RNA gain-of-function that leads to detrimental changes in RNA metabolism. (bvsalud.org)
Toxic8
These data demonstrate a robust reduction of toxic RNA foci, a hallmark of this repeat expansion disorder, in the nucleus as well as the correction of splicing and a significant reduction of myotonia with Cas13d and PUF constructs via different mechanisms of action," said John Leonard, Ph.D., chief scientific officer at Locanabio. (locanabio.com)
Additionally, the data demonstrate our ability to preferentially target the toxic, mutant allele and preserve DMPK RNA generated from the wild-type allele, which is one of several distinguishing features of our CORRECTx platform. (locanabio.com)
The expanded CTG is transcribed into toxic CUG repeats in the DMPK RNA. (locanabio.com)
These toxic RNA repeats lead to disease symptoms including progressive muscle wasting, weakness and myotonia (delayed relaxation of skeletal muscle), a hallmark of DM1. (locanabio.com)
Expansion's approach to treating DM1 is focused on designing novel small molecule drugs that can selectively bind the disease-causing toxic CUG repeats in DMPK mRNA and liberate key sequestered proteins so that they can function properly. (expansionrx.com)
Expansion's approach to treating DM1 is focused on designing novel small molecule medicines that can selectively bind the disease-causing toxic r(CUG) structures in DMPK RNA. (expansionrx.com)
Herein, we demonstrate molecular and physiological amelioration of the toxic effects of mutant RNA in the HSA(LR) mouse model of DM1 by systemic administration of peptide-linked morpholino (PPMO) antisense oligonucleotides bearing a CAG repeat sequence. (bvsalud.org)
The disease mechanism for these untranslated repeats is called the "toxic RNA hypothesis. (medicalhomeportal.org)
Alleles1
In addition, much of the evidence for the mechanisms that are thought to produce repeat expansion in pathological TNRs are dismissed as irrelevant for normal alleles. (bmj.com)
Proteins2
The close relationship of DMPK to the Rho-kinases has led to speculation whether DMPK activity may be regulated in vivo by small G proteins, particularly of the Rho family. (wikipedia.org)
In this disease model, the excessive CTG repeats bind RNA binding proteins important in splicing (editing) other RNAs besides DMPK. (medicalhomeportal.org)
Molecular2
6- 8 Expansions in the number of TNRs are known to be a molecular basis of genetic anticipation, 9 the progressively earlier age of onset of a disease with increasing severity in successive generations. (bmj.com)
The diagnosis of DM1 is suspected in individuals with characteristic muscle weakness and is confirmed by molecular genetic testing of DMPK . (nih.gov)
Contractions1
As the DMPK repeat is replicated, the hairpin loop that is formed leads to repeat expansion (a) or contractions (b). (wikipedia.org)
Abnormal2
CTG repeat length exceeding 34 repeats is abnormal. (nih.gov)
It is one of the many examples of neurologic diseases, such as Huntington disease and fragile X syndrome, that are caused by an excessive number of such repeats (a CTG repeat length of 35 or more is abnormal). (medicalhomeportal.org)
Mutations2
10 These factors are not mutually exclusive and include the purity and length of the repeated sequence, 7, 11 age of individuals, 6, 7 mitotic drive, 12 the relative position of the TNR with respect to adjacent origins of DNA replication, 13 and mutations in genes involved in DNA repair, replication, and recombination. (bmj.com)
The 2 forms, type 1 and type 2, are caused by different gene mutations. (medicalhomeportal.org)
Bind1
These CUG repeats form stable, RNA structures which in turn bind to and sequester a protein called muscleblind (MB). (expansionrx.com)
Severe1
The classification describes a continuum ranging from mild to severe disease, which generally correlates with trinucleotide repeat (CTG) length. (medicalhomeportal.org)
Disorder2
Hundreds of critical genes are therefore mis-spliced, leading to the diverse array of muscular, cardiac and neurological abnormalities seen in this disorder. (expansionrx.com)
A related disorder, DM2, is caused by a similar repeat expansion in the CNBP gene. (expansionrx.com)
Therapy1
1 Department of Gene Therapy & Regenerative Medicine, Vrije Universiteit Brussel, 1090 Brussels, Belgium. (nih.gov)
Form1
1000 repeats, though the congenital form may be seen with fewer repeats. (medicalhomeportal.org)
Disease2
Despite cloning of the locus, the complex disease phenotype of DM has proven difficult to interpret, and the exact role of DMPK in the pathogenesis of DM remains unclear. (wikipedia.org)
These findings suggest that CNS gene delivery of a silent anti-Aß scFv-IgG was well-tolerated, durably expressed and functional in a relevant disease model, demonstrating the potential of this modality for the treatment of Alzheimer's disease. (bvsalud.org)
Model1
Short-term activation of DMPK-1 and -2 may be mediated by transitory interaction with a small GTPase (G). A general model that accounts for DMPK oligomerization, processing, and regulation has been proposed. (wikipedia.org)
Transfer2
In addition, and in order to uncover a potential role of a functional mismatch repair (MMR) system in mutagen-induced TNR instability, all experiments were done in MMR proficient (SW480) or deficient cell lines (HCT116 and LoVo), as well as in the HCT116 cell line corrected for MMR deficiency by microcell mediated chromosome 3 transfer. (bmj.com)
Here, we show that single chain Abs fused to an Fc domain retaining FcRn binding, but lacking Fc gamma receptor (FcγR) binding, termed a silent scFv-IgG, can be expressed and released into the CNS following gene transfer with AAV. (bvsalud.org)
Brain1
In this way, the splicing of hundreds of genes will be corrected across multiple tissues, including brain and heart, as well as muscle, thus restoring function across the whole body. (expansionrx.com)