CNBP – Myotonic Dystrophy Type 2

This summary integrates evidence from multiple independent studies that link pathogenic repeat expansions in CNBP (formerly ZNF9) to myotonic dystrophy type 2. Case reports from diverse populations—including a Japanese patient showing a unique ancestral haplotype (PMID:18057971) and a juvenile onset case co‑segregating with a recessive CLCN1 mutation (PMID:22407275)—demonstrate that CNBP repeat expansions are consistently observed in patients with this multisystem disorder. Further, multi‑patient cohort studies have confirmed these findings across over 40 patients from varied ethnic backgrounds (PMID:21224892), reinforcing the genetic evidence supporting this association.

Genetic investigations reveal that the expansion of a tetranucleotide CCTG repeat in intron 1 of CNBP confers an autosomal dominant inheritance pattern. Multiple families exhibit clear segregation of the expansion with typical symptoms such as proximal muscle weakness, cataract, and white matter abnormalities (PMID:22332444). Though a specific coding sequence variant in standard HGVS format was not provided, the documented repeat expansion remains the pathogenic mutation underlying the disease.

Functional studies further reveal that mutant CNBP alleles lead to abnormal mRNA splicing and reduced protein expression (PMID:20971734). In addition, CNBP has been shown to be part of an ITAF ribonucleoprotein complex that modulates cap‑independent translation, offering mechanistic insights into its role in disease pathogenesis (PMID:17327219).

While some studies have examined co‑occurring mutations in other genes, the weight of evidence from segregation analyses, case reports, and functional validation firmly supports a strong role for CNBP repeat expansions in causing myotonic dystrophy type 2.

In summary, the convergence of robust genetic and experimental evidence makes CNBP an essential diagnostic marker for myotonic dystrophy type 2. The clinical utility of this association is high, both for diagnostic decision‑making and for informing further research and commercial genetic testing strategies.

References

• Neurogenetics • 2008 • Myotonic dystrophy type 2 in Japan: ancestral origin distinct from Caucasian families PMID:18057971
• Journal of Neurology • 2012 • Co-segregation of DM2 with a recessive CLCN1 mutation in juvenile onset of myotonic dystrophy type 2 PMID:22407275
• European Journal of Human Genetics • 2011 • Dutch myotonic dystrophy type 2 patients and a North-African DM2 family carry the common European founder haplotype PMID:21224892
• The Israel Medical Association Journal • 2011 • Clinical, electrophysiologic and pathologic findings in 10 patients with myotonic dystrophy 2 PMID:22332444
• The American Journal of Pathology • 2010 • Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2 PMID:20971734
• Molecular & Cellular Proteomics • 2007 • The myotonic dystrophy type 2 protein ZNF9 is part of an ITAF complex that promotes cap-independent translation PMID:17327219

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