Abstract：
:Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia with a strong genetic component. Molecular pathways involving the homeodomain transcription factor Shox2 control the development and function of the cardiac conduction system in mouse and zebrafish. Here we report the analysis of human SHOX2 as a potential susceptibility gene for early-onset AF. To identify causal variants and define the underlying mechanisms, results from 378 patients with early-onset AF before the age of 60 years were analyzed and compared to 1870 controls or reference datasets. We identified two missense mutations (p.G81E, p.H283Q), that were predicted as damaging. Transactivation studies using SHOX2 targets and phenotypic rescue experiments in zebrafish demonstrated that the p.H283Q mutation severely affects SHOX2 pacemaker function. We also demonstrate an association between a 3'UTR variant c.*28T>C of SHOX2 and AF (p = 0.00515). Patients carrying this variant present significantly longer PR intervals. Mechanistically, this variant creates a functional binding site for hsa-miR-92b-5p. Circulating hsa-miR-92b-5p plasma levels were significantly altered in AF patients carrying the 3'UTR variant (p = 0.0095). Finally, we demonstrate significantly reduced SHOX2 expression levels in right atrial appendages of AF patients compared to patients with sinus rhythm. Together, these results suggest a genetic contribution of SHOX2 in early-onset AF.
journal_name
Basic Res Cardioljournal_title
Basic research in cardiologyauthors
Hoffmann S,Clauss S,Berger IM,Weiß B,Montalbano A,Röth R,Bucher M,Klier I,Wakili R,Seitz H,Schulze-Bahr E,Katus HA,Flachsbart F,Nebel A,Guenther SP,Bagaev E,Rottbauer W,Kääb S,Just S,Rappold GAdoi
10.1007/s00395-016-0557-2subject
Has Abstractpub_date
2016-05-01 00:00:00pages
36issue
3eissn
0300-8428issn
1435-1803pii
10.1007/s00395-016-0557-2journal_volume
111pub_type
杂志文章abstract：:A rapid change in length of cat papillary muscle induces two reciprocal diastolic and systolic processes: stretching causes a viscoelastic relaxation of the muscle. The opposite behavior is observed after abrupt releases when - subsequent to an increase in resting tension - diastolic force attains its new equilibrium....
journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/978-3-662-11374-5_15
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journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：
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journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF02650875
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
pub_type： 杂志文章,评审
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journal_title：Basic research in cardiology
pub_type： 杂志文章
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journal_title：Basic research in cardiology
pub_type： 杂志文章,评审
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journal_title：Basic research in cardiology
pub_type： 杂志文章
doi：10.1007/BF02005337
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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journal_title：Basic research in cardiology
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更新日期：1993-01-01 00:00:00
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journal_title：Basic research in cardiology
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