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http://purl.uniprot.org/citations/22247482http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/22247482http://www.w3.org/2000/01/rdf-schema#comment"

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.

Methods and 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."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.org/dc/terms/identifier"doi:10.1161/circep.111.967604"xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Horie M."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Watanabe H."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Mugishima H."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Mochizuki N."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Roden D.M."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Fukuhara S."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Delmar M."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Le Marec H."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Seki A."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Makiyama T."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Makita N."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Bezzina C.R."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Shimizu W."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Wilde A.A."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Sumitomo N."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Hagiwara N."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Schott J.J."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Probst V."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Baron E."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Hasdemir C."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Chkourko H."xsd:string
http://purl.uniprot.org/citations/22247482http://purl.uniprot.org/core/author"Baruteau A."xsd:string
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