DM2_CNBP
- Gene
- CNBP
- Disease
- DM2
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 14.5
- Publications Reviewed
- 5
- Publication Span
- 15.99 years
- Last Updated
- 07/21/2025
- Curator(s)
- Laurel Hiatt
Description
Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystem disorder caused by a CCTG repeat expansion in intron 1 of CNBP (formerly ZNF9). Genetic evidence includes genetically confirmed DM2 families with the expansion, allele-level differences between interrupted normal alleles and uninterrupted expanded alleles, and linkage/segregation support across European-origin kindreds. Experimental evidence supports toxic expanded CCUG RNA effects, including RNA foci, MBNL-dependent mis-splicing, disrupted Drosophila retinal morphology/apoptosis with partial molecular rescue by PKR inhibition, and altered CNBP/ZNF9 expression and splicing in DM2 patient muscle.
Genetic evidence
Total: 8.5
| Singular Evidence | Probands | PMID:14505273 | 6 | Haplotype analysis of 71 families with genetically confirmed DM2; all affected individuals were diagnosed with DM and tested positive for the CNBP/ZNF9 CCTG expansion. |
| Collective Evidence | Allele | PMID:11486088 | 1 | DM2 alleles showed uninterrupted expansion of the CCTG portion of the intron 1 repeat tract (75–~11,000 repeats; mean ~5,000), whereas sequenced normal alleles were interrupted and controls showed no expansion. |
| Collective Evidence | Segregation | PMID:12970845 | 1.5 | Linkage analysis across 17 European-origin PROMM/PDM/DM2 kindreds gave a peak multipoint LOD score of 19.521 at D3S3584; all affected individuals had the CNBP/ZNF9 CCTG expansion. |
Experimental evidence
Total: 6
| Models | Non-human model organism | PMID:28623239 | 2 | Drosophila DM2-106 model expressing noncoding (CCUG)106 repeats recapitulated DM2-like RNA foci, MBNL-dependent mis-splicing, retinal/eye disruption, and apoptosis. |
| Function | Regulatory impact | PMID:28623239 | 0.5 | In DM2-106 fly muscle, expanded CCUG repeats caused aberrant Fhos exon 24 inclusion (>70% vs ~30% in controls) and altered INSR, TNNT2, and Tnnt3 spliceosensor reporters. |
| Function | Biochemical function | PMID:28623239 | 0.5 | Expanded (CCUG)106 transcripts formed predominantly nuclear RNA foci in fly muscle and retinal cells and sequestered MBNL proteins. |
| Functional Alteration | Non-patient cells | PMID:28623239 | 0.5 | Expression of DM2-106 in Drosophila retina disrupted photoreceptor, cone, and pigment cell organization and induced apoptosis in developing eye imaginal discs. |
| Rescue | Rescue in non-human model organism | PMID:28623239 | 2 | PKR-I treatment reduced/disrupted CCUG RNA foci and apoptosis in DM2-106 eye imaginal discs; the paper notes adult eye morphology was not rescued after larval feeding. |
| Function | Regulatory impact | PMID:20971734 | 0.5 | In DM2 skeletal muscle, the mutant CNBP/ZNF9 allele showed retention of intron 1 sequences and aberrant intron 3-retaining transcripts, consistent with impaired splicing and reduced mRNA/protein levels. |
| Functional Alteration | Patient cells | PMID:20971734 | 1 | Patient skeletal muscle biopsies and myoblast cultures from genetically confirmed DM2 cases showed reduced CNBP/ZNF9 mRNA/protein, altered localization, and aberrant splicing compared with normal and DM1 controls. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.