Abstract:
AIMS:Nonsense mutations in the SCN5A gene result in truncated, non-functional derivatives of the cardiac Na+ channel and thus cause arrhythmias. Studies of other genes suggest that pathogenic phenotypes of nonsense mutations may be alleviated by enhancing readthrough, which enables ribosomes to ignore premature termination codons and produce full-length proteins. Thus, we studied the functional restoration of nonsense-mutated SCN5A. METHODS AND RESULTS:HEK293 cells were transfected with SCN5A cDNA or its mutant carrying W822X, a nonsense mutation associated with Brugada syndrome and sudden cardiac death. The effects of readthrough-enhancing reagents on Na+ channel expression and function were examined in the transfected cells. W822X robustly reduced Na+ current, decreasing maximal Na+ current to <3% of the wild-type level, and inhibited the expression of full-length Na+ channels. When readthrough was enhanced by either reducing translational fidelity with aminoglycosides or decreasing translation termination efficiency with small-interfering RNA against eukaryotic release factor eRF3a, Na+ current of the mutant was restored to approximately 30% of the wild-type level; western blot and immunochemical staining analyses showed the increased expression of full-length channels. When the wild-type and mutant cDNAs were co-transfected, readthrough-enhancing reagents increased Na+ current from 56% to 74% of the wild-type level. Analysis of Na+ channel kinetics showed that the channels expressed from the mutant cDNA under readthrough-enhancing conditions retained the functions of wild-type channels. CONCLUSION:Readthrough-enhancing reagents can effectively suppress SCN5A nonsense mutations and may restore the expression of full-length Na+ channels with normal functions, which might prevent sudden cardiac death in mutation carriers.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Teng S,Gao L,Paajanen V,Pu J,Fan Zdoi
10.1093/cvr/cvp116subject
Has Abstractpub_date
2009-08-01 00:00:00pages
473-80issue
3eissn
0008-6363issn
1755-3245pii
cvp116journal_volume
83pub_type
杂志文章abstract::Activation of sphingosine kinase/sphingosine-1-phosphate (SK/S1P)-mediated signalling has been recognized as critical for cardioprotection in response to acute ischaemia/reperfusion injury. Incubation of S1P with cultured cardiac myocytes subjected to hypoxia or treatment of isolated hearts either before ischaemia or ...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvn309
更新日期:2009-05-01 00:00:00
abstract:OBJECTIVE:The aim was to further characterise an experimental model of preconditioning of isolated rabbit cardiomyocytes and to determine the role of adenosine receptor subtypes in initiation of the protective response. METHODS:Isolated myocytes were subjected to 5 min preincubation in the presence or absence of gluco...
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doi:10.1093/cvr/28.7.1049
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journal_title:Cardiovascular research
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doi:10.1016/j.cardiores.2003.11.024
更新日期:2004-02-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1093/cvr/cvv176
更新日期:2015-09-01 00:00:00
abstract:AIMS:Polyunsaturated fatty n-3 acids (PUFAs) have been reported to exhibit antiarrhythmic properties. However, the mechanisms of action remain unclear. We studied the electrophysiological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on IKs, and on the expression and location of Kv7.1 and KCNE1....
journal_title:Cardiovascular research
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doi:10.1093/cvr/cvu250
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/25.3.184
更新日期:1991-03-01 00:00:00
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journal_title:Cardiovascular research
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更新日期:2018-09-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvy257
更新日期:2019-03-15 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2005.02.004
更新日期:2005-06-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvw049
更新日期:2016-06-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1016/0008-6363(96)00052-1
更新日期:1996-08-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/20.1.36
更新日期:1986-01-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/s0008-6363(97)00141-7
更新日期:1997-08-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvp360
更新日期:2010-03-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1016/s0008-6363(99)00231-x
更新日期:1999-12-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/26.11.1116
更新日期:1992-11-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.7.1359
更新日期:1993-07-01 00:00:00
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更新日期:2013-12-01 00:00:00
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doi:10.1016/s0008-6363(99)00194-7
更新日期:1999-10-01 00:00:00
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更新日期:2006-04-01 00:00:00
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journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/17.5.251
更新日期:1983-05-01 00:00:00
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pub_type: 杂志文章
doi:10.1093/cvr/cvn085
更新日期:2008-08-01 00:00:00
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doi:10.1016/j.cardiores.2006.03.017
更新日期:2006-07-01 00:00:00
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更新日期:2010-09-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1093/cvr/10.2.254
更新日期:1976-03-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1093/cvr/25.8.676
更新日期:1991-08-01 00:00:00
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journal_title:Cardiovascular research
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doi:10.1093/cvr/20.7.536
更新日期:1986-07-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.cardiores.2003.12.018
更新日期:2004-03-01 00:00:00