title: A connexin40 mutation associated with a malignant variant of progressive familial heart block type I.
abstract: BACKGROUND
  Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His-Purkinje system. PFHBI has been linked to genes such as SCN5A that influence cardiac excitability but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phenotype correlation for that mutation.
  
  
  RESULTS
  We screened 156 probands with PFHBI. In addition to 12 sodium channel mutations, we found a germ line GJA5 (connexin40 [Cx40]) mutation (Q58L) in 1 family. Heterologous expression of Cx40-Q58L in connexin-deficient neuroblastoma cells resulted in marked reduction of junctional conductance (Cx40-wild type [WT], 22.2±1.7 nS, n=14; Cx40-Q58L, 0.56±0.34 nS, n=14; P<0.001) and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions. Heteromeric cotransfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in ≈50% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques.
  
  
  CONCLUSIONS
  Mutation Cx40-Q58L impairs gap junction formation at cell-cell interfaces. This is the first demonstration of a germ line mutation in a connexin gene that associates with inherited ventricular arrhythmias and emphasizes the importance of Cx40 in normal propagation in the specialized conduction system.
authors.affiliation: Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. makitan@nagasaki-u.ac.jp
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Akiko
authors.initials: A
authors.lastname: Seki
authors.forename: Naokata
authors.initials: N
authors.lastname: Sumitomo
authors.forename: Halina
authors.initials: H
authors.lastname: Chkourko
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Fukuhara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Can
authors.initials: C
authors.lastname: Hasdemir
authors.forename: Hideo
authors.initials: H
authors.lastname: Mugishima
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Alban
authors.initials: A
authors.lastname: Baruteau
authors.forename: Estelle
authors.initials: E
authors.lastname: Baron
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Hagiwara
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002036:Bundle of His / Q000378:metabolism* / Q000503:physiopathology; D000075224:Cardiac Conduction System Disease; D002648:Child; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D020022:Genetic Predisposition to Disease; D006327:Heart Block / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011379:Prognosis; D000097003:Gap Junction alpha-5 Protein
chemical_list: D015415:Biomarkers; D017630:Connexins; D004247:DNA; D000097003:Gap Junction alpha-5 Protein