Document Detail


Defining the cellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes.
MedLine Citation:
PMID:  17242276     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. METHODS AND RESULTS: We performed a comprehensive screen of ANK2 in populations (control, congenital arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a spectrum of cellular phenotypes. We then characterized the relative severity of loss-of-function properties of all 9 nonsynonymous ANK2 variants identified to date in primary cardiomyocytes and identified a range of in vitro phenotypes, including wild-type, simple loss-of-function, and severe loss-of-function activity, seen with the variants causing severe human phenotypes. CONCLUSIONS: We present the first description of differences in cellular phenotypes conferred by specific ANK2 variants. We propose that the various degrees of ankyrin-B loss of function contribute to the range of severity of cardiac dysfunction. These data identify ANK2 variants as modulators of human arrhythmias, provide the first insight into the clinical spectrum of "ankyrin-B syndrome," and reinforce the role of ankyrin-B-dependent protein interactions in regulating cardiac electrogenesis.
Authors:
Peter J Mohler; Solena Le Scouarnec; Isabelle Denjoy; John S Lowe; Pascale Guicheney; Lise Caron; Iwona M Driskell; Jean-Jacques Schott; Kris Norris; Antoine Leenhardt; Richard B Kim; Denis Escande; Dan M Roden
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-01-22
Journal Detail:
Title:  Circulation     Volume:  115     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-01-30     Completed Date:  2007-02-20     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  432-41     Citation Subset:  AIM; IM    
Affiliation:
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, USA. peter-mohler@uiowa.edu
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MeSH Terms
Descriptor/Qualifier:
African Continental Ancestry Group / genetics
Aged
Animals
Ankyrins / genetics*
Arrhythmias, Cardiac / chemically induced,  ethnology*,  genetics*
Asian Continental Ancestry Group / genetics
Cytoskeleton / physiology
European Continental Ancestry Group / genetics
Female
Genetic Variation*
Genotype
Humans
Ion Channels / physiology
Long QT Syndrome / chemically induced,  ethnology,  genetics
Male
Mexican Americans / genetics
Mice
Mice, Inbred C57BL
Middle Aged
Myocytes, Cardiac / cytology,  physiology*
Phenotype
Tachycardia, Ventricular / chemically induced,  ethnology,  genetics
Torsades de Pointes / chemically induced,  ethnology,  genetics
Grant Support
ID/Acronym/Agency:
HL65962/HL/NHLBI NIH HHS; R01HL083422/HL/NHLBI NIH HHS; R01HL084583/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/ANK2 protein, human; 0/Ankyrins; 0/Ion Channels
Comments/Corrections
Comment In:
Circulation. 2007 Jan 30;115(4):428-9   [PMID:  17261669 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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