A Muscleblind Knockout Model for Myotonic Dystrophy

  title={A Muscleblind Knockout Model for Myotonic Dystrophy},
  author={Rahul N. Kanadia and Karen A. Johnstone and Ami Mankodi and Codrin Lungu and Charles A. Thornton and Douglas W. Esson and Adrian M. Timmers and William W. Hauswirth and Maurice S. Swanson},
  pages={1978 - 1980}
The neuromuscular disease myotonic dystrophy (DM) is caused by microsatellite repeat expansions at two different genomic loci. Mutant DM transcripts are retained in the nucleus together with the muscleblind (Mbnl) proteins, and these abnormal RNAs somehow interfere with pre-mRNA splicing regulation. Here, we show that disruption of the mouse Mbnl1 gene leads to muscle, eye, and RNAsplicing abnormalities that are characteristic of DM disease. Our results support the hypothesis that… 

RNA-mediated neuromuscular disorders.

Evidence that similar mechanisms may play a role in a growing number of dominant noncoding expansion disorders, including fragile X tremor ataxia syndrome (FXTAS), spinocerebellarAtaxia type 8 (SCA8), SCA10, SCA12, and Huntington's disease-like 2 (HDL2) is discussed.

Nuclear RNA Foci in the Heart in Myotonic Dystrophy

Evidence is reported for a parallel mechanism in the heart of myotonic dystrophy type 1 that sequestration of RNA binding proteins in nuclear foci of expanded poly(CUG) RNA contributes to cardiac disease in DM1.


An overview of the DM splicing mis-regulation will be presented, with focus on mis- regulation of the BIN1 mRNA, which plays an important role in tubular invaginations of the plasma membrane and is required for biogenesis of T-tubules, which are specialized membrane structures essential for excitation-contraction coupling.

Two ways to misregulate mRNAs in myotonic dystrophy

Two mouse models for myotonic dystrophy—mice expressing expanded CUG repeats and mice lacking functional MBNL1—now reveal ∼100 new mis-splicing events and a new class of aberrantly regulated mRNAs.

Genetics and molecular pathogenesis of the myotonic dystrophies

  • J. DayL. Ranum
  • Medicine, Biology
    Current neurology and neuroscience reports
  • 2005
Clinical and molecular characterization of myotonic dystrophy types 1 and 2 have now demonstrated a novel disease mechanism involving pathogenic effects of repeat expansions that are expressed in RNA but are not translated into protein.

Novel Drosophila model of myotonic dystrophy type 1: phenotypic characterization and genome-wide view of altered gene expression.

Comparative transcriptional profiling performed on the generated DM1 lines and on the muscleblind (mbl)-RNAi line revealed that nuclear accumulation of toxic CUG repeats can affect gene expression independently of splicing or Mbl sequestration, and the largest portion of deregulated genes corresponded to single-transcript genes, revealing an unexpected impact of the indirect influence of mbl on gene expression.

Altered mRNA splicing of dystrophin in type 1 myotonic dystrophy

It is suggested that the aberrantly spliced dystrophin is responsible for the muscle wasting in DM1.

Myotonic Dystrophy and Developmental Regulation of RNA Processing.

A comprehensive overview of DM1 and DM2 clinical presentation and pathology as well as the underlying cellular and molecular defects associated with DM disease onset and progression is provided.

Pathogenic mechanisms of myotonic dystrophy.

The RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders are focused on.

Flies deficient in Muscleblind protein model features of myotonic dystrophy with altered splice forms of Z-band associated transcripts

The results point to similarities but subtle differences in the molecular breakdown of Z-band structures in flies and DM patients and emphasise the relevance of Muscleblind proteins in DM pathophysiology.



Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3' untranslated region of the DMPK gene. The mutant DMPK messenger

[Myotonic dystrophy].

  • E. Nanba
  • Medicine
    Nihon rinsho. Japanese journal of clinical medicine
  • 2005
The clinical features common to both diseases are caused by a gain of function RNA mechanism in which the CUG and CCUG repeats alter cellular function, and the long PCR based method is useful for the molecular diagnosis for these diseases.

Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy

This work proposes that DM1 disease is caused by aberrant recruitment of the EXP proteins to the DMPK transcript (CUG)n expansion, and identifies the triplet repeat expansion (EXP) RNA‐binding proteins as candidate sequestered factors.

Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2.

The results support the idea that nuclear accumulation of mutant RNA is pathogenic in DM1, suggest that a similar disease process occurs in DM2, and point to a role for muscleblind in the pathogenesis of both disorders.

Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of ZNF9

DM2 is caused by a CCTG expansion located in intron 1 of the zinc finger protein 9 (ZNF9) gene, indicating that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.

Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy.

Data presented here indicate that the conserved heterogeneous nuclear ribonucleoprotein, CUG-binding protein (CUG-BP), may mediate the trans-dominant effect of the RNA.

DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model.

It is demonstrated that D MPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy.

Dominantly inherited, non-coding microsatellite expansion disorders.

In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts

Using a combination of indirect immunofluorescence to detect endogenous proteins and overexpression of proteins with green fluorescent protein (GFP) tags, it is shown that CUG-BP and hnRNP C do not co-localise with expanded repeat foci in DM1 cell lines.