English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel

Schweizer, P. A., Schröter, J., Greiner, S., Haas, J., Yampolsky, P., Mereles, D., et al. (2014). The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. Journal of the American College of Cardiology, 64(8), 757-767. doi:10.1016/j.jacc.2014.06.1155.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0023-CDC8-5 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0023-CDC9-3
Genre: Journal Article

Files

show Files
hide Files
:
JAmCollegCardio_64_2014_757.pdf (Any fulltext), 3MB
 
File Permalink:
-
Name:
JAmCollegCardio_64_2014_757.pdf
Description:
-
Visibility:
Restricted (Max Planck Institute for Medical Research, MHMF; )
MIME-Type / Checksum:
application/pdf
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Creators

show
hide
 Creators:
Schweizer, Patrick A., Author
Schröter, Julian, Author
Greiner, Sebastian, Author
Haas, Jan, Author
Yampolsky, Pessah, Author
Mereles, Derliz, Author
Buss, Sebastian J., Author
Seyler, Claudia, Author
Bruehl, Claus, Author
Draguhn, Andreas, Author
Koenen, Michael1, Author              
Meder, Benjamin, Author
Katus, Hugo A., Author
Thomas, Dierk, Author
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              

Content

show
hide
Free keywords: HCN4; noncompaction cardiomyopathy; overlap syndrome; sinus node dysfunction
 Abstract: BACKGROUND: Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM). OBJECTIVES: The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis. METHODS: The index family and a cohort of unrelated probands with sinus bradycardia were examined by electrocardiography, Holter recording, exercise stress test, echocardiography, and/or cardiac magnetic resonance imaging. Targeted next-generation and direct sequencing were used for candidate gene analysis and mutation scanning. Ion channels were expressed in HEK293 cells and studied using patch-clamp recordings. RESULTS: SND and biventricular NCCM were diagnosed in multiple members of a German family. Segregation analysis suggested autosomal-dominant inheritance of the combined phenotype. When looking for potentially disease-causing gene variants with cosegregation, a novel hyperpolarization-activated cyclic nucleotide channel 4 (HCN4)-G482R mutation and a common cysteine and glycine-rich protein 3 (CSRP3)-W4R variant were identified. HCN4-G482R is located in the highly conserved channel pore domain. Mutant subunits were nonfunctional and exerted dominant-negative effects on wild-type current. CSRP3-W4R has previously been linked to dilated and hypertrophic cardiomyopathy, but was also found in healthy subjects. Moreover, different truncation (695X) and missense (P883R) HCN4 mutations segregated with a similar combined phenotype in an additional, unrelated family and a single unrelated proband respectively, which both lacked CSRP3-W4R. CONCLUSIONS: The symptom complex of SND and NCCM is associated with heritable HCN4 defects. The NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families.

Details

show
hide
Language(s): eng - English
 Dates: 2014-05-262014-02-262014-06-022014-08-182014-08-26
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.jacc.2014.06.1155
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Journal of the American College of Cardiology
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 64 (8) Sequence Number: - Start / End Page: 757 - 767 Identifier: ISSN: 1133-4304
CoNE: https://pure.mpg.de/cone/journals/resource/110978984252272