Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene

Sabouri, Luc A.; Mahadevan, Mani S.; Narang, Monica A.; Lee, David S. C.; Surh, Linda; Korneluk, Robert G.

doi:10.1038/ng0793-233

Cited by 136 publications

(58 citation statements)

References 44 publications

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“…This work extends the original observations of Roses and Appel linking DM to membrane protein phosphorylation (13)(14)(15) and reconfirms the role of HMPK as the active agent in DM (5,36,37). Moreover, these findings link the pathophysiology of DM (altered Na channel kinetics to the genetic abnormality) a mutation in a gene whose product has sequence similarity to protein kinases.…”

Section: Discussionsupporting

confidence: 69%

Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

Mounsey

John

et al. 1995

J. Clin. Invest.

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In myotonic muscular dystrophy, abnormal muscle Na currents underlie myotonic discharges. Since the myotonic muscular dystrophy gene encodes a product, human myotonin protein kinase, with structural similarity to protein kinases, we tested the idea that human myotonin protein kinase modulates skeletal muscle Na channels. Coexpression of human myotonin protein kinase with rat skeletal muscle Na channels in Xenopus oocytes reduced the amplitude of Na currents and accelerated current decay. The effect required the presence of a potential phosphorylation site in the inactivation mechanism of the channel. The mutation responsible for human disease, trinucleotide repeats in the 3' untranslated region, did not prevent the effect. The consequence of an abnormal amount of the kinase would be altered muscle cell excitability, consistent with the clinical finding of myotonia in myotonic dystrophy. (J. Clin. Invest. 1995. 95:2379-2384

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Section: Discussionsupporting

confidence: 69%

Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

Mounsey

John

et al. 1995

J. Clin. Invest.

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“…These studies suggest that the triplet repeat expansion results in decreased steady-state levels of myotonin mRNA from the expanded allele; however, they do not distinguish between RNA stability and gene transcription. In contrast, at least one report (11) demonstrates increased abundance of myotonin mRNA in skeletal muscle from an affected individual, and the effect of the trinucleotide repeat expansion on steady-state mRNA levels remains controversial.…”

Section: Resultsmentioning

confidence: 85%

“…The general population has <37 repeats, and affected individuals have between 50 and thousands of repeats, with phenotype being correlated with expansion size (2)(3)(4)(5)(6). Lower levels of myotonin mRNA and protein have been demonstrated in patients with myotonic dystrophy (7)(8)(9)(10); however, another study described increased amounts of myotonin mRNA in tissues of an affected neonate (11). A recent study (12) demonstrated that CTG repeats created strong nucleosome positioning signals when nucleosomes were reconstituted on DNA in vitro.…”

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confidence: 99%

Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.

Otten

Tapscott²

1995

Proc. Natl. Acad. Sci. U.S.A.

172

107

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Myotonic dystrophy is caused by an expansion of a CTG triplet repeat sequence in the 3' noncoding region of a protein kinase gene, yet the mechanism by which the triplet repeat expansion causes disease remains unknown. This report demonstrates that a DNase I hypersensitive site is positioned 3' of the triplet repeat in the wild-type allele in both fibroblasts and skeletal muscle cells. In three unrelated individuals with myotonic dystrophy that have large expansions of the triplet repeat, the allele with the triplet repeat expansion exhibited both overall DNase I resistance and inaccessibility of nucleases to the adjacent hypersensitive site. These results indicate that the triplet repeat expansion alters the adjacent chromatin structure, establishing a region of condensed chromatin, and suggests a molecular mechanism for myotonic dystrophy.

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“…Decreased expression of steady state DMK transcript levels (9) or of mutant gene transcripts (10,11) have been reported, as well as decreased levels of a 52-55-kDa protein product in patients (9,12), consistent with a haploinsufficiency model. In contrast, we have noted mutant gene transcript expression and DMK transcript overexpression in congenital tissues (13). More recently, two studies using allelespecific quantitative reverse transcription PCR systems detected no (14) or a small (15) decrease in total DMK transcripts.…”

Section: Myotonic Dystrophy (Dm)mentioning

confidence: 93%

Investigation of Myotonic Dystrophy Kinase Isoform Translocation and Membrane Association

Waring

Haq

Tamai

et al. 1996

Journal of Biological Chemistry

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Myotonic dystrophy is caused by the expansion of a CTG repeat found in the 3-untranslated region of the myotonic dystrophy kinase. The mechanism of disease and the role of the kinase are currently obscure. Here we begin the investigation of domain structure/function correlations to aid in determining its normal function.Expressed full-length protein and protein truncated before a C-terminal hydrophobic domain were compared. In vitro, signal peptide function and protection of kinase by microsomal membranes were absent; thus, it is not translocated, as previously proposed. However, full-length kinase expressed in insect cells was found in fractions enriched for membranes and decorated mitochondria. The truncated form was found primarily in the cytosol. The kinase was present as two self-associated, disulfide-linked complexes. The majority of fulllength kinase was found in the larger of the two complexes, while almost all of the truncated form was found in the smaller. Thus, the C-terminal region confers a higher order of self-association. Furthermore, fulllength kinase expressed in COS-1 cells was present as high molecular weight complex, while the truncated form was present as monomer species. These experiments indicate that the myotonic dystrophy kinase is not membrane-integrated, but that it may have a molecular organization which favors peripheral association with membranes.

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Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene

Cited by 136 publications

References 44 publications

Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.

Investigation of Myotonic Dystrophy Kinase Isoform Translocation and Membrane Association

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