| DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model. | |
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MedLine Citation:
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PMID: 10021468 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Myotonic dystrophy (DM) is the most common form of muscular dystrophy and is caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the principal cardiac manifestation of this disease. The etiology of the pathophysiological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodomain protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects observed in DM. Using an in vivo murine electrophysiology study, we show that cardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPK-/- mice develop cardiac conduction defects which include first-, second-, and third-degree atrioventricular (A-V) block. Our results demonstrate that the A-V node and the His-Purkinje regions of the conduction system are specifically compromised by DMPK loss. Importantly, DMPK+/- mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy. |
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Authors:
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C I Berul; C T Maguire; M J Aronovitz; J Greenwood; C Miller; J Gehrmann; D Housman; M E Mendelsohn; S Reddy |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 103 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 1999 Feb |
Date Detail:
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Created Date: 1999-04-13 Completed Date: 1999-04-13 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: R1-7 Citation Subset: AIM; IM |
Affiliation:
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Department of Cardiology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. berul@cardio.tch.harvard.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cholinergic Agents Disease Models, Animal Female Gene Dosage* Heart Block / genetics*, physiopathology Male Mice Mutagenesis Myocardium / pathology Myotonic Dystrophy / genetics*, physiopathology Protein-Serine-Threonine Kinases / genetics, physiology* Sympatholytics |
| Grant Support | |
ID/Acronym/Agency:
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HL-03607/HL/NHLBI NIH HHS; HL-41484/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cholinergic Agents; 0/Sympatholytics; EC 2.7.1.-/myotonic dystrophy protein kinase; EC 2.7.11.1/Protein-Serine-Threonine Kinases |
| Comments/Corrections | |
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