title: Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
authors.forename: Ninda
authors.initials: N
authors.lastname: Syam
authors.affiliation: 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.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chatel
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
authors.forename: Lijo Cherian
authors.initials: LC
authors.lastname: Ozhathil
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
authors.forename: Valentin
authors.initials: V
authors.lastname: Sottas
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Rougier
authors.affiliation: 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.
authors.forename: Alban
authors.initials: A
authors.lastname: Baruteau
authors.affiliation: 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.
authors.forename: Estelle
authors.initials: E
authors.lastname: Baron
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
authors.forename: Mohamed-Yassine
authors.initials: MY
authors.lastname: Amarouch
authors.affiliation: 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Daumy
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.affiliation: 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.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.affiliation: 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.
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
mesh_terms: D054537:Atrioventricular Block / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D002304:Cardiac Pacing, Artificial; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010138:Pacemaker, Artificial; D018408:Patch-Clamp Techniques; D017510:Protein Folding; D021381:Protein Transport / Q000235:genetics*; D057165:Proteostasis Deficiencies / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism; D013696:Temperature
chemical_list: D050053:TRPM Cation Channels; C437888:TRPM4 protein, human
keywords: atrioventricular block; mutations; temperature‐dependent rescue; transient receptor potential melastatin member 4