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

@article{Liquori2001MyotonicDT,
  title={Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of ZNF9},
  author={Christina L. Liquori and Kenneth Ricker and Melinda L. Moseley and Jennifer F. Jacobsen and Wolfram Kress and S. L. Naylor and John W. Day and Laura P. W. Ranum},
  journal={Science},
  year={2001},
  volume={293},
  pages={864 - 867}
}
Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3′ untranslated region of the dystrophia myotonica–protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report… 
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1,169 Citations

Pathogenic mechanisms of myotonic dystrophy.

TLDR
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.

Myotonic dystrophy: Clinical and molecular parallels between myotonic dystrophy type 1 and type 2

  • L. RanumJ. Day
  • Medicine
    Current neurology and neuroscience reports
  • 2002
TLDR
The recent discovery that DM2 is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that 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, including alternative splicing of various genes.

SPLICING ABNORMALITIES IN MYOTONIC DYSTROPHIES

TLDR
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.

RNA-mediated neuromuscular disorders.

TLDR
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.

Myotonic dystrophy: emerging mechanisms for DM1 and DM2.

Myotonic dystrophy: RNA pathogenesis comes into focus.

TLDR
The recent discovery that myotonic dystrophy type 2 (DM2) is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that 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, including alternative splicing of various genes.

[Myotonic dystrophy - a new insight into a well-known disease].

Molecular Diagnosis of Myotonic Dystrophy

TLDR
The clinical phenotypes, genetic mutations causing the diseases, and the molecular diagnostic approaches and tools that are used to determine repeat sizes in DM1/2 are reviewed and discussed.

Biomolecular identification of (CCTG)n mutation in myotonic dystrophy type 2 (DM2) by FISH on muscle biopsy.

TLDR
The consistent detection of ribonuclear inclusions in DM2 muscles and their absence in DM1, in agreement with the clinical diagnosis and with leukocyte (CCTG)n expansion, suggests that fluorescence in situ hybridization using (CAGG)5 probes, may be a specific method to distinguish between DM1 and DM2.

Myotonic Dystrophies Type 1 and 2

TLDR
Clinically DM 1 is characterised by muscle wasting primarily of the distal, axial, facial, pharyngeal and respiratory muscles, accompanied by cataracts, cardiac conduction blockade and arrhythmia, cardiomyopathy, diabetes, dysthyroidism and drowsiness.
...

References

SHOWING 1-10 OF 46 REFERENCES

Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene

TLDR
DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation in as, and the magnitude of this effect depends on the extent of CTG repeat expansion, which supports the hypothesis that DMAHP participates in the pathophysiology of DM.

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    BioEssays : news and reviews in molecular, cellular and developmental biology
  • 1998
TLDR
There is now circumstantial evidence that long (CTG)n repeats may affect the expression of any of at least three genes, myotonic dystrophy protein kinase (DMPK), DMR‐N9, and a DM‐associated homeodomain protein (DMAHP).

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TLDR
A five-generation family is identified with a genetically distinct form of myotonic dystrophy with remarkable clinical similarity to DM, and the disease locus (DM2) of the MN1 family is mapped to a 10-cM region of chromosome 3q.

Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP

TLDR
It is demonstrated that CTG-repeat expansions can suppress local gene expression and implicate DMAHP in DM pathogenesis by showing a two- to fourfold reduction in steady-state D MAHP transcript levels relative to wild-type controls.

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TLDR
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.

Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy

TLDR
The results indicate that D MPK may be necessary for the maintenance of skeletal muscle structure and function and suggest that a decrease in DMPK levels may contribute to DM pathology.

Myotonic dystrophy is associated with a reduced level of RNA from the DMWD allele adjacent to the expanded repeat.

TLDR
The level of the DM-associated allele in the cytoplasm ofDM cell lines is reduced by 20-50% compared with the wild-type allele, similar to the level of reduction found for SIX5 in allele-specific analysis, however, no such reduction is observed in RNA from the nuclear fraction of DM cell lines.

Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy

TLDR
The results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonia and cataracts represents a multigenic disorder.

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

TLDR
It is reported that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8), which is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.

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