title: Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I.
abstract: BACKGROUND
  Progressive cardiac conduction disease (PCCD) is one of the most common cardiac conduction disturbances. It has been causally related to rare mutations in several genes including SCN5A, SCN1B, TRPM4, LMNA and GJA5.
  
  
  RESULTS
  In this study, by applying targeted next-generation sequencing (NGS) in 95 unrelated patients with PCCD, we have identified 13 rare variants in the TRPM4 gene, two of which are currently absent from public databases. This gene encodes a cardiac calcium-activated cationic channel which precise role and importance in cardiac conduction and disease is still debated. One novel variant, TRPM4-p.I376T, is carried by the proband of a large French 4-generation pedigree. Systematic familial screening showed that a total of 13 family members carry the mutation, including 10 out of the 11 tested affected individuals versus only 1 out of the 21 unaffected ones. Functional and biochemical analyses were performed using HEK293 cells, in whole-cell patch-clamp configuration and Western blotting. TRPM4-p.I376T results in an increased current density concomitant to an augmented TRPM4 channel expression at the cell surface.
  
  
  CONCLUSIONS
  This study is the first extensive NGS-based screening of TRPM4 coding variants in patients with PCCD. It reports the third largest pedigree diagnosed with isolated Progressive Familial Heart Block type I and confirms that this subtype of PCCD is caused by mutation-induced gain-of-expression and function of the TRPM4 ion channel.
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Daumy
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lindenbaum
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bonnaud
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Charpentier
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bianchi
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Nafzger
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, 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: Swanny
authors.initials: S
authors.lastname: Fouchard
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Thollet
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Kyndt
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France.
authors.forename: Solena
authors.initials: S
authors.lastname: Le Scouarnec
authors.affiliation: Molecular Physiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Gourraud
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.affiliation: Department of Clinical Research, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland. Electronic address: Hugues.Abriel@dkf.unibe.ch.
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
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, l'institut du thorax, Nantes, France; Université de Nantes, l'institut du thorax, Nantes, France; Centre Hospitalier Universitaire (CHU) de Nantes, l'institut du thorax, Service de Cardiologie, Nantes, France. Electronic address: jjschott@univ-nantes.fr.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000075224:Cardiac Conduction System Disease; D002648:Child; D018450:Disease Progression; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D057809:HEK293 Cells; D006327:Heart Block / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*; D050053:TRPM Cation Channels / Q000235:genetics*
chemical_list: D050053:TRPM Cation Channels; C437888:TRPM4 protein, human
keywords: Atrio-ventricular block; Gain-of-function mutation; PFHBI; TRPM4