Myotonic Dystrophy 1 (DMPK)
| Dred_ID | RD00043 |
| OMIM ID | 160900 |
| Disease name | Myotonic Dystrophy 1 |
| Alternative names | Steinert's Disease Myotonic Dystrophy Type 1 Dm1 |
| Category | Genetic diseases, Rare diseases, Neuronal diseases, Eye diseases, Reproductive diseases, Endocrine diseases, Muscle diseases |
| Phenotype | NIH Rare Diseases: Myotonic dystrophy type 1 (MD1), one of the two types of myotonic dystrophy, is an inherited type of muscular dystrophy that affects the muscles and other body systems (e.g., heart, eyes, endocrine system, and central nervous system). MD1 has three forms that somewhat overlap: the mild form, classic form, and congenital form (present at birth). The mild form has the least severe symptoms of the different forms of MD1 and is associated with a normal life span. The classic form is characterized by muscle weakness and wasting, prolonged muscle tensing (myotonia), cataract, and often, abnormal heart function. Adults with the classic form may become physically disabled and may have a shortened life span. The congenital form is characterized by severe generalized weakness at birth (hypotonia), often causing complications with breathing and early death. MD1 is inherited in an autosomal dominant manner and is caused by mutations in the DMPK gene. Treatment is based on the signs and symptoms present.
OMIM: Myotonic dystrophy is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. The genetic defect in DM1 results from an amplified trinucleotide repeat in the 3-prime untranslated region of a protein kinase gene. Disease severity varies with the number of repeats: normal individuals have 5 to 37 repeats, mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with congenital onset can have more than 2,000 repeats. The disorder shows genetic anticipation, with expansion of the repeat number dependent on the sex of the transmitting parent. Alleles of 40 to 80 repeats are usually expanded when transmitted by males, whereas only alleles longer than 80 repeats tend to expand in maternal transmissions. Repeat contraction events occur 4.2 to 6.4% of the time (Musova et al., 2009). (160900) |
| Miscellaneouse | OMIM: genetic anticipation occurs prevalence of in 1 in 8,000 normal - 5 to 37 copies of (ctg)n repeat in dmpk affected, mild - 50-150 repeats adult onset - 100-1,000 repeats congenital - over 2,000 repeats negative repeat expansion (reverse anticipation) can occur (approximately 5% of the time) |
| Prevalence | 1-9/100000 (Europe),1-5/10000 (United Kingdom),1-5/10000 (Iceland),1-9/100000 (Serbia),1-9/100000 (Japan),1-9/1000000 (Taiwan, Province of China),1-5/10000 (South Africa),6-9/10000,>1/1000,1-9/1000000 (Serbia),1-9/100000 (Italy),1-5/10000 (Ireland),1-5/10000,1-9/100000,1-5/10000 (Croatia) [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | DMPK |
| Alias symbols | DM; DM1; DMK; MDPK; DM1PK; MT-PK |
| Gene name | DM1 protein kinase |
| Gene map locus | 19q13.32; chr19:45,769,717-45,782,490(-) |
| Ensembl Gene ID | ENSG00000104936 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | 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] |
| Repeat unit | CTG |
| Normal repeat copies | 5-37 |
| Pathogenic repeat copies | ≥50 |
| Gene | DMPK |
| Repeat location | 3' UTR |
| Chromosome locus | chr19:45770202-45770264 (-) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | RNA |
| Possible toxicity | The DM region of chromosome 19 is gene rich, and it is possible that the repeat expansion may lead to dysfunction of a number of transcription units in the vicinity, perhaps as a consequence of chromatin disruption. Boucher et al. (1995) searched for genes associated with a CpG island at the 3-prime end of DMPK. Sequencing of the region showed that the island extends over 3.5 kb and is interrupted by the (CTG)n repeat. Comparison of genomic sequences downstream (centromeric) of the repeat in human and mouse identified regions of significant homology. This led to the identification of the gene which Boucher et al. (1995) called 'DM locus-associated homeodomain protein' (DMAHP; 600963). They found that this protein is expressed in a number of human tissues, including skeletal muscle, heart, and brain.
Hino et al. (2007) identified motifs downstream of exon 22 of the SERCA1 gene that serve as MBNL1-binding motifs and positively regulate SERCA1 exon 22 splicing. Overexpression of the CUG repeat expansion of DMPK mRNA resulted in the exclusion of exon 22 of SERCA1. These results suggested that sequestration of MBNL1 into the CUG repeat expansion of DMPK mRNA caused the splicing defect and exclusion of SERCA1 exon 22. The expression of this aberrantly spliced SERCA1 could affect the regulation of calcium concentration of sarcoplasmic reticulum in DM1 patients. [By OMIM] |
| Pathway annotation | Reactome, KEGG |
| PMID | 24455202 |
| Authors | Judith R B, Aline H, Annie N, Arnold M, Genevieve G |
| Title | Transcriptionally Repressive Chromatin Remodelling and CpG Methylation in the Presence of Expanded CTG-Repeats at the DM1 Locus |
| Journal | J Nucleic Acids |
| Year | 2013 |
| PMID | 14671308 |
| Authors | Kanadia R N, Johnstone K A, Mankodi A, Lungu C, Thornton C A, Esson D, Timmers A M, Hauswirth W W, Swanson M S |
| Title | A muscleblind knockout model for myotonic dystrophy |
| Journal | Science. 302:1978-80 |
| Year | 2003 |