Manumycin A corrects aberrant splicing of Clcn1 in myotonic dystrophy type 1 (DM1) mice

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Abstract

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults and as yet no cure for DM1. Here, we report the potential of manumycin A for a novel DM1 therapeutic reagent. DM1 is caused by expansion of CTG repeat. Mutant transcripts containing expanded CUG repeats lead to aberrant regulation of alternative splicing. Myotonia (delayed muscle relaxation) is the most commonly observed symptom in DM1 patients and is caused by aberrant splicing of the skeletal muscle chloride channel ( CLCN1) gene. Identification of small-molecule compounds that correct aberrant splicing in DM1 is attracting much attention as a way of improving understanding of the mechanism of DM1 pathology and improving treatment of DM1 patients. In this study, we generated a reporter screening system and searched for small-molecule compounds. We found that manumycin A corrects aberrant splicing of Clcn1 in cell and mouse models of DM1.

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Most cited references 32

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The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.

K Scheffzek, M R Ahmadian, W Kabsch … (1997)

The three-dimensional structure of the complex between human H-Ras bound to guanosine diphosphate and the guanosine triphosphatase (GTPase)-activating domain of the human GTPase-activating protein p120GAP (GAP-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. The structure shows the partly hydrophilic and partly hydrophobic nature of the communication between the two molecules, which explains the sensitivity of the interaction toward both salts and lipids. An arginine side chain (arginine-789) of GAP-334 is supplied into the active site of Ras to neutralize developing charges in the transition state. The switch II region of Ras is stabilized by GAP-334, thus allowing glutamine-61 of Ras, mutation of which activates the oncogenic potential, to participate in catalysis. The structural arrangement in the active site is consistent with a mostly associative mechanism of phosphoryl transfer and provides an explanation for the activation of Ras by glycine-12 and glutamine-61 mutations. Glycine-12 in the transition state mimic is within van der Waals distance of both arginine-789 of GAP-334 and glutamine-61 of Ras, and even its mutation to alanine would disturb the arrangements of residues in the transition state.

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Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.

C Liquori (2001)

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 that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.

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

J. W. Miller (2000)

Myotonic dystrophy (DM1) is an autosomal dominant neuromuscular disorder associated with a (CTG)(n) expansion in the 3'-untranslated region of the DM1 protein kinase (DMPK) gene. To explain disease pathogenesis, the RNA dominance model proposes that the DM1 mutation produces a gain-of-function at the RNA level in which CUG repeats form RNA hairpins that sequester nuclear factors required for proper muscle development and maintenance. Here, we identify the triplet repeat expansion (EXP) RNA-binding proteins as candidate sequestered factors. As predicted by the RNA dominance model, binding of the EXP proteins is specific for dsCUG RNAs and proportional to the size of the triplet repeat expansion. Remarkably, the EXP proteins are homologous to the Drosophila muscleblind proteins required for terminal differentiation of muscle and photoreceptor cells. EXP expression is also activated during mammalian myoblast differentiation, but the EXP proteins accumulate in nuclear foci in DM1 cells. We propose that DM1 disease is caused by aberrant recruitment of the EXP proteins to the DMPK transcript (CUG)(n) expansion.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 05 July 2013

Publication date Collection: 2013

Volume: 3

Electronic Location Identifier: 2142

Affiliations

[1 ]Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo , Komaba, Tokyo, Japan

[2 ]Department of Neurology, Osaka University Graduate School of Medicine , Suita, Osaka, Japan

[3 ]Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry , Kodaira, Tokyo, Japan

[4 ]Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry , Kodaira, Tokyo, Japan

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[a ] cishiura@ 123456mail.ecc.u-tokyo.ac.jp

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Publisher Item ID: srep02142

DOI: 10.1038/srep02142

PMC ID: 3701899

PubMed ID: 23828222

SO-VID: 70c1287f-e160-41ff-b79c-7acc305dae01

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

Manumycin A corrects aberrant splicing of Clcn1 in myotonic dystrophy type 1 (DM1) mice

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Most cited references 32

The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.

Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.

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

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