This report describes myotonic dystrophy 1 (DM1), which is a subtype of myotonic dystrophy; DM1 exhibits autosomal dominant inheritance. The human gene implicated in this disease is dystrophia myotonica protein kinase (DMPK), which encodes a serine-threonine protein kinase that is closely related to other kinases that interact with members of the Rho family of small GTPases. Expanded (CTG)n repeats in the 3' UTR of DMPK are associated with DM1; it is one of several neurodegenerative diseases associated with expanded RNA repeats (see RNA repeat diseases, FBhh0000059). There is one moderately scoring fly ortholog of DMPK, gek, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical alleles have been generated.
Drosophila models of DM1 make use of UAS constructs driving runs of CTG repeats of variable length, independent of a protein-coding component; these are indicated as alleles of the synthetic gene Zzzz\CTG. Multiple UAS constructs of the CTG trinucleotide repeat have been introduced into flies, including wild-type low copy number repeats, disease-associated expanded repeats, and interrupted CTG repeats.
A UAS construct of a tagged human Hsap\DMPK gene has been introduced into flies, but has not been characterized in the context of this disease model.
The pathogenicity of the expanded RNA repeats in both DM1 and DM2 appear to involve dysregulation of the RNA-binding muscleblind proteins MBNL1, MBNL2, and MBNL3. The orthologous Drosophila gene, mbl, has been extensively characterized, including in the context of RNA-repeat disease.
[updated May 2022 by FlyBase; FBrf0222196]
Myotonic dystrophy is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. [From MIM:608233, 2016.04.15]
[MYOTONIC DYSTROPHY 1; DM1](https://omim.org/entry/160900)
[DYSTROPHIA MYOTONICA PROTEIN KINASE; DMPK](https://omim.org/entry/605377)
Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. The clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital. Mild DM1 is characterized by cataract and mild myotonia (sustained muscle contraction); life span is normal. Classic DM1 is characterized by muscle weakness and wasting, myotonia, cataract, and often cardiac conduction abnormalities; adults may become physically disabled and may have a shortened life span. Congenital DM1 is characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; intellectual disability is common. [from GeneReviews, Myotonic Dystrophy Type 1, pubmed:20301344 2016.04.19]
Myotonic dystrophy is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes (Musova et al., 2009, pubmed:9514047). In adult-onset DM1, symptoms typically become evident in middle life, but signs can be detectable in the second decade. Unlike the other muscular dystrophies, DM initially involves the distal muscles of the extremities and only later affects the proximal musculature. In addition, there is early involvement of the muscles of the head and neck. Involvement of the extraocular muscles produces ptosis, weakness of eyelid closure, and limitation of extraocular movements. Atrophy of masseters, sternocleidomastoids, and the temporalis muscle produces a characteristic haggard appearance. Both myotonia and weakness are observed in patients with swallowing and speech disability. Myotonia, delayed muscular relaxation following contraction, is most frequently apparent in the tongue, forearm, and hand. Myotonia is rarely as severe as in myotonia congenita and tends to be less apparent as weakness progresses (Bosma and Brodie, 1969, pubmed:5762063). [From MIM:160900, 2016.04.15]
Myotonic dystrophy-1 (DM1) is caused by a heterozygous trinucleotide repeat expansion (CTG)n in the 3-prime untranslated region of the dystrophia myotonica protein kinase gene (DMPK). [From MIM:160900 and MIM:605377, 2016.04.15]
Many of the muscle biopsy changes are nonspecific. Most commonly there are central nuclei and ring fibers. Necrosis, regeneration, and increase of collagen are never as severe as in Duchenne muscular dystrophy. In 70% of patients there is hypotrophy of type I muscle fibers; less commonly there are markedly atrophic fibers (Casanova and Jerusalem, 1979, pubmed:442988). In many cases there are target fibers, suggesting neurogenic dysfunction, but intramuscular nerves appear histologically normal (Drachman and Fambrough, 1976, pubmed:938274). Ultrastructural studies show dilatation of T tubules or sarcoplasmic reticulum, whose contents may be unusually dense (Fardeau et al., 1965). In some cases the surface membrane may be irregular, with reduplication of basal lamina. [From MIM:160900, 2016.04.18]
The DMPK gene encodes a serine-threonine protein kinase that is closely related to other kinases that interact with members of the Rho family of small GTPases. [Gene Cards, DMPK; 2017.05.16]
The pathogenesis of both DM1 and DM2 can be explained by a gain-of-function RNA mechanism in which the CUG and CCUG repeats, respectively, alter cellular function, including alternative splicing of various genes [Tapscott & Thornton, 2001, pubmed:11486078; Ranum & Day 2002, pubmed:12169228; Ranum & Day 2004, pubmed:15065017; Day & Ranum 2005, pubmed:15676109). Both DM1 and DM2 have RNA foci containing RNA of the abnormally expanded allele that colocalize with several forms of the RNA-binding protein muscleblind (MBNL1, MBNL2, and MBNL3) ((Mankodi et al., 2001, pubmed:11590133; Fardaei et al., 2002, pubmed:11929853). [from GeneReviews, Myotonic Dystrophy Type 2, pubmed:20301639 2016.04.19]
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, pubmed:9514047). [From MIM:160900, 2016.04.15]
Nuclear foci are present in muscle sections taken from patients with symptomatic myotonic dystrophy 1 or myotonic dystrophy 2. Muscleblind (MBNL1, MIM:606516) proteins, which interact with expanded CUG repeats in vitro, localiz to the nuclear foci in both DM1 and DM2. It has been proposes that nuclear accumulation of mutant RNA is pathogenic in DM1, a similar disease process may occur in DM2, and muscleblind may play a role in the pathogenesis of both disorders (Mankodi et al., 2001, pubmed:11590133). Two additional human muscleblind-like genes, MBNL2 (MIM:607327) and MBNL3 (MIM:300413) expressed predominantly in the placenta. Green fluorescent protein-tagged versions of MBNL1, MBNL2, and MBNL3 colocalize with nuclear foci in DM1 and DM2 cells, suggesting that all 3 proteins may play a role in myotonic dystrophy pathophysiology (Fardaei et al., 2002, pubmed:11929853). In postmortem DM1 brain tissue, mutant DMPK transcripts are widely expressed in cortical and subcortical neurons. The mutant transcripts accumulate in discrete foci within neuronal nuclei. MBNL1 is recruited into the RNA foci and depleted elsewhere in the nucleoplasm. In parallel, a subset of neuronal pre-mRNAs showed abnormal regulation of alternative splicing (Jiang et al., 2004, pubmed:15496431). [From MIM:606516, 2016.04.26]
Many to one: 4 human to 1 Drosophila.
