It is a monogenic, autosomal dominant disease caused by an abnormal trinucleotide expansion in a region of the DMPK gene. (tmcnet.com)
These include spinal and bulbar muscular atrophy ( trinucleotide expansion in the AR gene), dentatorubral-pallidoluysian atrophy ( trinucleotide expansion in the DRPLA gene), spinocerebellar ataxia type 1 ( trinucleotide expansion in the SCA1gene), Machado-Joseph disease ( trinucleotide expansion in the SCA3 gene), myotonic dystrophy ( trinucleotide expansion in the DMPK gene), and Friedreich's ataxia ( a trinuncleotide expansion in the X25 gene). (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)
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)
Type 1 DM (DM1) involves expansion of a CTG trinucleotide repeat of the DMPK gene located on chromosome 19. (msdmanuals.com)
Dystrophy Type3
WALTHAM, Mass., Sept. 20, 2023 (GLOBE NEWSWIRE) -- Dyne Therapeutics, Inc. (Nasdaq: DYN), a clinical-stage muscle disease company focused on advancing innovative life-transforming therapeutics for people living with genetically driven diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for DYNE-101 for the treatment of myotonic dystrophy type 1 (DM1). (tmcnet.com)
DYNE-101 is an investigational therapeutic being evaluated in the Phase 1/2 global ACHIEVE clinical trial for people living with myotonic dystrophy type 1 (DM1). (tmcnet.com)
The major forms of MD include Duchenne MD (DMD), Becker MD (BMD), limb-girdle MD (LGMD), facioscapulohumeral dystrophy (FSHD), myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), congenital MD (CMD), oculopharyngeal MD (OPMD), distal MD (DMD), and Emery-Dreifuss MD (EDMD). (medscape.com)
Nucleotides4
A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. (medlineplus.gov)
A slippage event normally occurs when a sequence of repetitive nucleotides (tandem repeats) are found at the site of replication. (wikipedia.org)
Tandem repeats are unstable regions of the genome where frequent insertions and deletions of nucleotides can take place, resulting in genome rearrangements. (wikipedia.org)
Nucleotide excision repair proteins are mobilized to this area where one likely outcome is the expansion of nucleotides in the template strand while the other is the absence of nucleotides. (wikipedia.org)
An abnormal congenital condition, associated with defects in the LAMIN TYPE A gene, which is characterized by premature aging in children, where all the changes of cell senescence occur. (lookformedical.com)
Autosomal dominant2
Myotonic dystrophy is rare, autosomal dominant muscle disorder. (msdmanuals.com)
Myotonic dystrophy (DM) is the most common autosomal dominant muscular dystrophy and encompasses both skeletal muscle and cardiac complications. (jci.org)
Sequences3
Within DNA trinucleotide repeat sequences, the repair of DNA damage by the processes of homologous recombination, non-homologous end joining, DNA mismatch repair or base excision repair may involve strand slippage mispairing leading to trinucleotide repeat expansion when the repair is completed. (wikipedia.org)
Genomic regions with a high proportion of repeated DNA sequences (tandem repeats, microsatellites) are prone to strand slippage during DNA replication and DNA repair. (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)
Many human diseases have been reported to be associated with trinucleotide repeat expansions including Huntington's disease. (wikipedia.org)
An individual who is not affected by Huntington's disease will have 6-35 tandem repeats at the HD locus. (wikipedia.org)
The expansion of the HD locus results in a dysfunctional protein leading to Huntington's disease. (wikipedia.org)
Contraction4
It is a form of mutation that leads to either a trinucleotide or dinucleotide expansion, or sometimes contraction, during DNA replication. (wikipedia.org)
Although trinucleotide contraction is possible, trinucleotide expansion occurs more frequently. (wikipedia.org)
Symptoms and signs of myotonic dystrophy begin during adolescence or young adulthood and include myotonia (delayed relaxation after muscle contraction, which may be asymptomatic or described as muscle stiffness), weakness and wasting of distal limb muscles (especially in the hand) and facial muscles (ptosis is especially common), and cardiomyopathy. (msdmanuals.com)
Are capable of sensing contraction and expansion of ECF volume. (abcmedicalnotes.com)
Nucleotide2
Myotonic dystrophy is nucleotide repeat expansion disorder in which type 1 (DM1) is due to a trinucleotide repeat expansion on chromosome 19 and type 2 (DM2) arises from a tetranucleotide repeat expansion on chromosome 3. (jci.org)
Developing representative models of myotonic dystrophy in animals has been challenging due to instability of nucleotide repeat expansions, especially for DM2 which is characterized by nucleotide repeat expansions often greater than 5000 copies. (jci.org)
Type 2 DM (DM2) is milder and involves a CCTG repeat expansion mutation of the cellular nucleic acid binding protein gene CNBP (previously known as ZFN9) on chromosome 3q21.3. (msdmanuals.com)
Chromosome1
All homologous chromosome pairs contain two variant forms of the same gene , called " alleles ," which are passed down from parent to offspring. (amboss.com)
Unstable1
DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. (medlineplus.gov)
Genetic2
Аутосомно-домінантний Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. (msdmanuals.com)
Genetic disorders result from new or inherited gene mutations . (amboss.com)
Sequence4
If these repeats are found in coding regions then the variations to the polynucleotide sequence can result in the formation of abnormal proteins in eukaryotes. (wikipedia.org)
For example, insertion of a single repeat unit in GAGAGA expands the sequence to GAGAGAGA, while insertion of two repeat units in [GA]6 would produce [GA]8. (wikipedia.org)
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)
Epigenetic regulation of gene expression encompasses mechanisms that allow regulating the expression of the genes without modification of the DNA sequence. (amboss.com)
Protein4
Furthermore, we believe that these results could signal the potential for the accumulation of exon 51 skipped transcript and dystrophin protein in muscle tissue with repeated doses of PGN-EDO51 in people living with DMD. (tipranks.com)
Therefore, replication slippage leads to a form of trinucleotide expansion which results in serious changes to protein structure. (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)
It is structurally different from TELOMERIC REPEAT BINDING PROTEIN 1 in that it contains basic N-terminal amino acid residues. (lookformedical.com)
Insertions are thought to be self-accelerating: as repeats grow longer, the probability of subsequent mispairing events increases. (wikipedia.org)
Allele1
If expression of a trait requires only one copy of a gene (one allele). (msdmanuals.com)
Cellular1
This expansion of CTG repeats causes toxic RNA to cluster in the nucleus, forming nuclear foci and altering the splicing of multiple proteins essential for normal cellular function. (tmcnet.com)
Deletions1
Whole exome sequencing is not suitable for detecting polynucleotide repeat disorders or large insertion/deletions. (medlink.com)
Disorders2
This expansion causes the features of some disorders to become more severe with each successive generation. (medlineplus.gov)
Next-generation sequencing of the whole exome is useful for testing for multiple candidate genes simultaneously or for discovering new, rare disorders. (medlink.com)
Encodes1
The Bloom syndrome gene (BLM) encodes a RecQ-like DNA helicase. (lookformedical.com)
Copies1
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)
Replication4
When DNA polymerase encounters a direct repeat, it can undergo a replication slippage. (wikipedia.org)
Slippage occurs through five main stages: In the first step, DNA polymerase encounters the direct repeat during the replication process. (wikipedia.org)
DNA polymerase reassembles its position on the template strand and resumes normal replication, but during the course of reassembling, the polymerase complex backtracks and repeats the insertion of deoxyribonucleotides that were previously added. (wikipedia.org)
Tandem repeats (the main influence for slippage replication) can be found in coding and non-coding regions. (wikipedia.org)
Metabolism1
We herein demonstrated that circadian clock network in the intestines plays pivotal roles in skeletal metabolism such that the lack of Bmal1 gene in the intestines (Bmal1Int-/- mice) caused bone loss with bone resorption being activated and bone formation suppressed. (jci.org)
Occurs1
In the event that a slippage event occurs there can be a large expansion in the tandem repeats of the HD gene. (wikipedia.org)
Expression3
RNA-sequencing from DM1 and DM2 iPSC-derived cardiomyocytes revealed distinct misregulation of gene expression as well as differential aberrant splicing patterns. (jci.org)
We showed previously that cytoplasmic release of mtDNA activates the cGAS STING TBK1 pathway resulting in interferon-stimulated gene (ISG) expression that promotes antiviral immunity4. (regenerativemedicine.net)
Here, we find that persistent mtDNA stress is not associated with basally activated NF-κB signalling or interferon gene expression typical of an acute antiviral response. (regenerativemedicine.net)
Expand1
Insertions can expand simple tandem repeats by one or more units. (wikipedia.org)
Present2
However, an affected individual will have 36- 121 repeats present. (wikipedia.org)
Occasionally, myotonic dystrophy is present at birth in children of mothers and, rarely, fathers with DM1 mutations. (msdmanuals.com)
Human2
The HD gene is found in all human genomes. (wikipedia.org)
Human genetics is the study of the human genome and the transmission of genes from one generation to the next. (amboss.com)
Pairs1
The newly synthesized strand then detaches from the template strand and pairs with another direct repeat upstream. (wikipedia.org)
Muscle1
The term dystrophy (from Greek dys-, "difficult or abnormal," and trophe, "nutrition") is also a misnomer based on descriptions from over 150 years ago, when lack of growth nutrients was blamed for damaging muscle. (medscape.com)
Found1
This results in some repeats found in the template strand being replicated twice into the daughter strand. (wikipedia.org)
Parent1
The number of repeats can change as the gene is passed from parent to child. (medlineplus.gov)
Single1
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)
Central1
MRI features of spinal cord infarction are central T2 hyperintensity without significant cord expansion or contrast enhancement. (abcmedicalnotes.com)