Haploinsuffciency for Znf9 in Znf9− Mice Is Associated with Multiorgan Abnormalities Resembling Myotonic Dystrophy

Chen, Wei; Wang, Yucheng; Abe, Yoko; Cheney, Lukas; Udd, Bjarne; Li, Yiping

doi:10.1016/j.jmb.2007.01.088

Cited by 78 publications

(90 citation statements)

References 36 publications

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“…Our results also help to explain the observation that ZNF9 heterozygous knockout mice in the absence of toxic (CCUG) DM2 transcripts exhibit a number of DM2 features, 19 where reduction of ZNF9 levels in heterozygous Znf9 ϩ/Ϫ knockout mice has been shown to be sufficient to produce multiorgan symptoms resembling those of DM, including myotonia, muscular dystrophy, and cardiac defects. Taken together with our findings of reduced mRNA and protein levels in patients with DM2, it is likely that ZNF9 haploinsufficiency accounts for some of the DM2-specific manifestations.…”

Section: Discussionsupporting

confidence: 54%

“…has been demonstrated by the use of knockout mouse models for dystrophia myotonica protein kinase and ZNF9 19,28 both of which have phenotypic aspects of DM. Moreover, reduction of ZNF9 protein levels has been demonstrated in myoblasts from patients with DM2.…”

Section: Discussionmentioning

confidence: 99%

“…16 Two studies-one using four immortalized lymphoblastoid cell lines, 17 the other primary myoblast cultures from a heterozygous and a homozygous patient 18 -showed no effect of the (CCTG) DM2 expansion on ZNF9 mRNA and protein levels. 17,18 However, heterozygous Znf9 ϩ/Ϫ knockout mice developed a multiorgan phenotype resembling DM, 19 and recently a growing number of studies showed that ZNF9 may not be normally expressed in DM2 muscle. 20 -22 Thus, the DM2 phenotype may not depend solely on the expression of toxic mutant (CCUG) DM2 transcripts, but may also be due to alterations in ZNF9 expression.…”

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confidence: 99%

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Mutant (CCTG)n Expansion Causes Abnormal Expression of Zinc Finger Protein 9 (ZNF9) in Myotonic Dystrophy Type 2

Raheem

Olufemi

Bachinski

et al. 2010

The American Journal of Pathology

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The mutation that underlies myotonic dystrophy type 2 (DM2) is a (CCTG)n expansion in intron 1 of zinc finger protein 9 (ZNF9). It has been suggested that ZNF9 is of no consequence for disease pathogenesis. We determined the expression levels of ZNF9 during muscle cell differentiation and in DM2 muscle by microarray profiling, real-time RT-PCR, splice variant analysis, immunofluorescence, and Western blotting. Our results show that in differentiating myoblasts, ZNF9 protein was localized primarily to the nucleus, whereas in mature muscle fibers, it was cytoplasmic and organized in sarcomeric striations at the Z-disk. In patients with DM2 , ZNF9 was abnormally expressed. First, there was an overall reduction in both the mRNA and protein levels. Second, the subcellular localization of the ZNF9 protein was somewhat less cytoplasmic and more membrane-bound. Third, our splice variant analysis revealed retention of intron 3 in an aberrant isoform, and fourth quantitative allelespecific expression analysis showed the persistence of intron 1 sequences from the abnormal allele, further suggesting that the mutant allele is incompletely spliced. Thus, the decrease in total expression appears to be due to impaired splicing of the mutant transcript. Our data indicate that ZNF9 expression in DM2 patients is altered at multiple levels. Although toxic RNA effects likely explain overlapping phenotypic manifestations between DM1 and DM2, abnormal ZNF9 levels in DM2 may account for the differences in DM1.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mutant (CCTG)n Expansion Causes Abnormal Expression of Zinc Finger Protein 9 (ZNF9) in Myotonic Dystrophy Type 2

Raheem

Olufemi

Bachinski

et al. 2010

The American Journal of Pathology

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“…As mentioned previously, CELF1 protein levels increase in DM and CELF1 overexpression in transgenic mice inhibits myogenesis and causes MEF2A and p21 overexpression (Timchenko et al, 2004). Several studies have suggested that DM2 is caused by CNBP haploinsufficiency (Chen et al, 2007; Huichalaf et al, 2009; Raheem et al, 2010) although other groups report that CNBP protein levels are not altered in this disease (Botta et al, 2006; Margolis et al, 2006; Massa et al, 2010). Interestingly, CNBP binds to the 5′ UTRs of terminal oligopyrimidine (TOP) genes encoding a variety of proteins important for translational regulation, including PABPC1, eIF1a and eIF2, so CCUG exp expression has been proposed to impact the rate of global protein synthesis (Huichalaf et al, 2009; Schneider-Gold & Timchenko, 2010).…”

Section: 2 Rna Toxicity and Protein Sequestration In Myotonic Dystrmentioning

confidence: 99%

RNA-Binding Protein Misregulation in Microsatellite Expansion Disorders

Goodwin

Swanson

2014

Advances in Experimental Medicine and Biology

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RNA-binding proteins (RBPs) play pivotal roles in multiple cellular pathways from transcription to RNA turnover by interacting with RNA sequence and/or structural elements to form distinct RNA-protein complexes. Since these complexes are required for the normal regulation of gene expression, mutations that alter RBP functions may result in a cascade of deleterious events that lead to severe disease. Here, we focus on a group of hereditary disorders, the microsatellite expansion diseases, which alter RBP activities and result in abnormal neurological and neuromuscular phenotypes. While many of these diseases are classified as adult-onset disorders, mounting evidence indicates that disruption of normal RNA-protein interaction networks during embryogenesis modifies developmental pathways which ultimately leads to disease manifestations later in life. Efforts to understand the molecular basis of these disorders has already uncovered novel pathogenic mechanisms, including RNA toxicity and repeat-associated non-ATG (RAN) translation, and current studies suggest that additional surprising insights into cellular regulatory pathways will emerge in the future.

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“…[3–5] The rCCUG exp transcript may effect the expression levels of the ZNF9 protein, and this may contribute to the DM2 phenotype, however the reports on this point are somewhat contradictory. [4–8] …”

Section: Introductionmentioning

confidence: 99%

Small Molecules that Target the Toxic RNA in Myotonic Dystrophy Type 2

et al. 2014

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Myotonic dystrophy type 2 is caused by an expansion of CCTG repeats in the zinc-finger protein gene (ZNF9). Transcribed CCUG repeats sequester MBNL1, an important alternative splicing regulator, preventing its normal function, leading to the disease phenotype. We describe a series of ligands that disrupt the MBNL1-r(CCUG)n interaction as potential lead agents for developing DM2 therapeutics. A previously reported triaminopyrimidine-acridine conjugate was a moderate inhibitor in vitro, however it proved to be poorly water-soluble and not cell-permeable. To improve its therapeutic potential, the new set of ligands maintained the key triaminopyrimidine recognition unit but replaced the acridine intercalator with a bisamidinium groove binder. The optimized ligands exhibit low micromolar inhibition potency to MBNL1-r(CCUG)8. Importantly, the ligands are the first to show the ability to disrupt the MBNL1-r(CCUG)n foci in DM2 model cell culture and exhibit low cellular cytotoxicity.

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Haploinsuffciency for Znf9 in Znf9− Mice Is Associated with Multiorgan Abnormalities Resembling Myotonic Dystrophy

Cited by 78 publications

References 36 publications

Mutant (CCTG)n Expansion Causes Abnormal Expression of Zinc Finger Protein 9 (ZNF9) in Myotonic Dystrophy Type 2

Mutant (CCTG)n Expansion Causes Abnormal Expression of Zinc Finger Protein 9 (ZNF9) in Myotonic Dystrophy Type 2

RNA-Binding Protein Misregulation in Microsatellite Expansion Disorders

Small Molecules that Target the Toxic RNA in Myotonic Dystrophy Type 2

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