Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block.
- Syam N Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
- Chatel S Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, l'institut du thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
- Ozhathil LC Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
- Sottas V Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
- Rougier JS Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
- Baruteau A Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, l'institut du thorax, Nantes, France Marie Lannelongue Hospital, Department of Pediatric Cardiac Surgery, Paris Sud University, Paris, France.
- Baron E Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, l'institut du thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France.
- Amarouch MY Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
- Daumy X Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, l'institut du thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France.
- Probst V Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, l'institut du thorax, Nantes, France Université de Nantes, France Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
- Schott JJ Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, l'institut du thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France jjschott@univ-nantes.fr hugues.abriel@dkf.unibe.ch.
- Abriel H Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland jjschott@univ-nantes.fr hugues.abriel@dkf.unibe.ch.
- 2016-05-22
Published in:
- Journal of the American Heart Association. - 2016
atrioventricular block
mutations
temperature‐dependent rescue
transient receptor potential melastatin member 4
Atrioventricular Block
Cardiac Pacing, Artificial
Cell Membrane
Child
Child, Preschool
Female
Genetic Variation
HEK293 Cells
Humans
Infant
Infant, Newborn
Male
Pacemaker, Artificial
Patch-Clamp Techniques
Protein Folding
Protein Transport
Proteostasis Deficiencies
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
TRPM Cation Channels
Temperature
English
BACKGROUND
Transient receptor potential melastatin member 4 (TRPM4) is a nonselective cation channel. TRPM4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM4-dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM4 genetic variants found in patients with congenital or childhood atrioventricular block.
METHODS AND RESULTS
Ninety-one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare TRPM4 genetic variants were identified and investigated. The variants were expressed heterologously in HEK293 cells. Two of the variants, A432T and A432T/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole-cell patch-clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered SUMOylation of TRPM4 may cause a gain of function; however, we did not find any evidence that supports SUMOylation as being directly involved for the gain-of-function variant.
CONCLUSIONS
This study underpins the role of TRPM4 in the cardiac conduction system. The loss-of-function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding-dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies.
Transient receptor potential melastatin member 4 (TRPM4) is a nonselective cation channel. TRPM4 mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying TRPM4-dependent conduction slowing are not fully understood. The aim of this study was to characterize TRPM4 genetic variants found in patients with congenital or childhood atrioventricular block.
METHODS AND RESULTS
Ninety-one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare TRPM4 genetic variants were identified and investigated. The variants were expressed heterologously in HEK293 cells. Two of the variants, A432T and A432T/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole-cell patch-clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered SUMOylation of TRPM4 may cause a gain of function; however, we did not find any evidence that supports SUMOylation as being directly involved for the gain-of-function variant.
CONCLUSIONS
This study underpins the role of TRPM4 in the cardiac conduction system. The loss-of-function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding-dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1161/JAHA.114.001625
- PMID 27207958
- Persistent URL
- https://sonar.ch/global/documents/44936
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