{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:30:21Z","timestamp":1789907421459,"version":"4.0.1"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              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\n              <jats:italic>SCN5A<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              We screened 156 probands with PFHBI. In addition to 12 sodium channel mutations, we found a germ line\n              <jats:italic>GJA5<\/jats:italic>\n              (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\u00b11.7 nS, n=14; Cx40-Q58L, 0.56\u00b10.34 nS, n=14;\n              <jats:italic>P<\/jats:italic>\n              &lt;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 \u224850% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.111.967604","type":"journal-article","created":{"date-parts":[[2012,1,14]],"date-time":"2012-01-14T06:42:35Z","timestamp":1326523355000},"page":"163-172","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":68,"title":["A Connexin40 Mutation Associated With a Malignant Variant of Progressive Familial Heart Block Type I"],"prefix":"10.1161","volume":"5","author":[{"given":"Naomasa","family":"Makita","sequence":"first","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Seki","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naokata","family":"Sumitomo","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halina","family":"Chkourko","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigetomo","family":"Fukuhara","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Shimizu","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie R.","family":"Bezzina","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Hasdemir","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Mugishima","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeru","family":"Makiyama","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alban","family":"Baruteau","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Baron","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Horie","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhisa","family":"Hagiwara","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A.M.","family":"Wilde","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Probst","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Le Marec","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan M.","family":"Roden","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Mochizuki","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Jacques","family":"Schott","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. Mochizuki); Cardiology..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Delmar","sequence":"additional","affiliation":[{"name":"From the Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan (N. Makita); Cardiology, Tokyo Women's Medical University, Tokyo, Japan (A.S., N.H.); Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan (N.S., H.M.); Cardiology, New York University Medical School, New York, NY (H.C., M.D.); Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan (S.F., N. 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