title: RING finger protein RNF207, a novel regulator of cardiac excitation.
abstract: Two recent studies (Newton-Cheh, C. et al. (2009) Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399-406 and Pfeufer, A. et al. (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41, 407-414) identified an association, with genome-wide significance, between a single nucleotide polymorphism within the gene encoding RING finger protein 207 (RNF207) and the QT interval. We sought to determine the role of RNF207 in cardiac electrophysiology. Morpholino knockdown of RNF207 in zebrafish embryos resulted in action potential duration prolongation, occasionally a 2:1 atrioventricular block, and slowing of conduction velocity. Conversely, neonatal rabbit cardiomyocytes infected with RNF207-expressing adenovirus exhibited shortened action potential duration. Using transfections of U-2 OS and HEK293 cells, Western blot analysis and immunocytochemistry data demonstrate that RNF207 and the human ether-a-go-go-related gene (HERG) potassium channel interact and colocalize. Furthermore, RNF207 overexpression significantly elevated total and membrane HERG protein and HERG-encoded current density by ∼30-50%, which was dependent on the intact N-terminal RING domain of RNF207. Finally, coexpression of RNF207 and HSP70 increased HERG expression compared with HSP70 alone. This effect was dependent on the C terminus of RNF207. Taken together, the evidence is strong that RNF207 is an important regulator of action potential duration, likely via effects on HERG trafficking and localization in a heat shock protein-dependent manner.
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903.
authors.forename: Karim
authors.initials: K
authors.lastname: Roder
authors.affiliation: the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Werdich
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Li
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903.
authors.forename: Man
authors.initials: M
authors.lastname: Liu
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903.
authors.forename: Tae Yun
authors.initials: TY
authors.lastname: Kim
authors.affiliation: the Department of Biological Sciences, Wellesley College, Wellesley, Massachusetts 02481.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Organ-Darling
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903.
authors.forename: Karni S
authors.initials: KS
authors.lastname: Moshal
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Hwang
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903.
authors.forename: Bum-Rak
authors.initials: BR
authors.lastname: Choi
authors.affiliation: the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.affiliation: From the Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, Rhode Island 02903, Gideon_Koren@Brown.edu.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D054537:Atrioventricular Block / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000072237:ERG1 Potassium Channel; D004625:Embryo, Nonmammalian; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D056966:Excitation Contraction Coupling; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006321:Heart / Q000196:embryology / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D008969:Molecular Sequence Data; D060172:Morpholinos; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D011817:Rabbits; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D018840:HSP70 Heat-Shock Proteins; C000606913:KCNH2 protein, human; D060172:Morpholinos; C000595665:RNF207 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Action Potential Duration; Conduction Velocity; Endoplasmic Reticulum (ER); HERG; HSP70; Protein Complex; RNF207; SNP; Zebrafish