This report describes myotonic dystrophy 2 (DM2), which is a subtype of myotonic dystrophy; DM2 exhibits autosomal dominant inheritance. The human gene implicated in this disease is CCHC-type zinc finger nucleic acid binding protein (CNBP), a single-stranded-nucleic-acid-binding protein with seven zinc-finger domains. Expanded (CCTG)n repeats in the first intron of CNBP are associated with DM2; it is one of several neurodegenerative diseases associated with expanded RNA repeats (see RNA repeat diseases, FBhh0000059). There is is one high-scoring fly ortholog of CNBP, Dmel\CNBP, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical alleles have been generated.
A UAS construct of a tagged human Hsap\CNBP gene has been introduced into flies; heterologous rescue (functional complementation) has been demonstrated for the larval locomotion defects observed for Dmel\CNBP-knockdown.
A Drosophila model using knockdown of Dmel\CNBP in muscles has been used to address the question of whether depletion or reduced function of CNBP (independent of repeat mechanisms) plays a role in the DM2 phenotype. In both larvae and adults, RNAi-mediated knockdown of Dmel\CNBP in muscles results in locomotor defects. The role of Dmel\CNBP in regulation of polyamine biosynthesis has been investigated; rescue of the CNBP locomotor phenotype is observed using polyamine supplementation or overexpression of a gene involved in polyamine biosynthesis.
Most Drosophila models of DM2 make use of UAS constructs driving runs of CCTG repeats of variable length, independent of a protein-coding component; these are indicated as alleles of the synthetic gene Zzzz\CCTG. Multiple UAS constructs of the CCTG nucleotide repeat have been introduced into flies, including wild-type low copy number repeats and disease-associated expanded repeats.
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 Sep. 2021 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 2; DM2](https://omim.org/entry/602668)
[CCHC-TYPE ZINC FINGER NUCLEIC ACID-BINDING PROTEIN; CNBP](https://omim.org/entry/116955)
Myotonic dystrophy type 2 (DM2) is characterized by myotonia (90% of affected individuals) and muscle dysfunction (weakness, pain, and stiffness) (82%), and less commonly by cardiac conduction defects, iridescent posterior subcapsular cataracts, insulin-insensitive type 2 diabetes mellitus, and testicular failure. Although myotonia (involuntary muscle contraction with delayed relaxation) has been reported during the first decade, onset is typically in the third decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and weakness of the neck flexors and finger flexors. Subsequently, weakness occurs in the elbow extensors and the hip flexors and extensors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms. [from GeneReviews, Myotonic Dystrophy Type 2, pubmed:20301639 2016.04.19]
Myotonic dystrophy (DM) is a multisystem disorder and the most common form of muscular dystrophy in adults. Individuals with DM2 have muscle pain and stiffness, progressive muscle weakness, myotonia, male hypogonadism, cardiac arrhythmias, diabetes, and early cataracts. Other features may include cognitive dysfunction, hypersomnia, tremor, and hearing loss (summary by Heatwole et al., 2011, pubmed:21911698). [From MIM:602668, 2016.04.15]
The intronic CNBP repeat tract is a complex repeat comprising TG, TCTG, and CCTG tracts, in this order. Each repeat can vary in length. For normal alleles, the overall length of the CCTG portion ranges from 11 to 26 tetranucleotide repeats and typically includes 0-2 interruptions within the CCTG tract; most commonly these are individual GCTC and TCTG interruptions separately located within the CCTG tract. For pathogenic alleles only the CCTG repeat tract expands, without interruptions, resulting in overall repeat lengths of 75 to more than 11,000 pure CCTG tetranucleotide repeats. [Gene Reviews, Myotonic Dystrophy Type 2; 2022.04.27]
Myotonic dystrophy-2 (DM2/PROMM) is caused by heterozygous expansion of a CCTG repeat in intron 1 of CNBP, the gene encoding CCHC-type zinc finger nucleic acid binding protein (also known as ZNF9), a protein containing 7 zinc finger domains that is believed to function as an RNA-binding protein. [From MIM:602668 and MIM:116955, 2016.04.18]
Muscle pathology includes atrophic fibers, scattered severely atrophic fibers with pyknotic myonuclei, and marked proliferation of fibers with central nuclei (Day, et al., 1999, pubmed:10063831; Day, et al., 2003, pubmed:12601109; Schoser, et al., 2004, pubmed:14755494). [from GeneReviews, Myotonic Dystrophy Type 2, pubmed:20301639 2016.04.19]
The CNBP gene encodes a nucleic-acid binding protein with seven zinc-finger domains; it preferentially binds single-stranded DNA and RNA. [Gene Cards, CNBP; 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]
A CCTG repeat expansion in intron 1 of the CNBP (ZNF9) gene is responsible for myotonic dystrophy 2 (DM2). The range of expanded allele sizes is extremely broad, from 75 to approximately 11,000 CCTG repeats. The mean repeat length is about 5,000. The expanded CNBP RNA accumulates in discrete foci within the nucleus. CNBP contains 7 zinc finger domains and is thought to be an RNA-binding protein. It is broadly expressed, with the most abundant expression in heart and skeletal muscle, 2 tissues prominently affected in DM2. The similarity of mechanism of mutation between DM2 and DM1 (MIM:160900) is striking: a trinucleotide repeat expansion in the 3-prime untranslated region of the DMPK gene (MIM:605377) is responsible for DM1. Clinical and molecular parallels between DM1 and DM2 indicate that microsatellite expansions in RNA can themselves be pathogenic (Liquori et al, 2001, pubmed:11486088). [From MIM:116955, 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). [From MIM:606516, 2016.04.26]
Many to one: 2 human to 1 Drosophila.
High-scoring ortholog of human CNBP and ZCCHC13 (1 Drosophila to 2 human). Dmel\CNBP exhibits 34-38% identity and 45-49% similarity with the human genes.
