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Updated: Apr 25, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in
Patrick A Schweizer1, Julian Schröter2, Sebastian Greiner3
1Department of Cardiology, University of Heidelberg, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
Insights
Genetic defects in the HCN4 gene cause inherited arrhythmias like sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM). A common CSRP3 variant may worsen NCCM symptoms in some families.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Electrophysiology
Background:
- Inherited arrhythmias were previously viewed as isolated electrical defects.
- Emerging evidence links ion channel dysfunction to myocardial disorders.
- Genetic links between sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM) were unreported.
Purpose of the Study:
- Investigate a familial electromechanical disorder combining SND and NCCM.
- Identify the genetic basis of this combined cardiac phenotype.
Main Methods:
- Clinical evaluation including ECG, Holter, stress tests, and cardiac imaging.
- Next-generation and direct sequencing for candidate gene analysis.
- Functional studies of ion channels using patch-clamp electrophysiology.
Main Results:
- A German family exhibited SND and biventricular NCCM with autosomal-dominant inheritance.
- A novel HCN4-G482R mutation in the channel pore domain was identified, showing nonfunctional and dominant-negative effects.
- A common CSRP3-W4R variant was found, previously associated with other cardiomyopathies.
- Additional unrelated families showed similar phenotypes linked to other HCN4 mutations, without the CSRP3-W4R variant.
Conclusions:
- Heritable defects in the HCN4 gene are associated with the combined phenotype of SND and NCCM.
- A common CSRP3 variant may exacerbate the NCCM phenotype in certain families.
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.
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