Vincenzo Macri1,2, Saagar N Mahida1,2, Michael L Zhang1, Moritz F Sinner1,3,4, Elena V Dolmatova1,2, Nathan R Tucker1,2, Micheal McLellan1, Marisa A Shea5, David J Milan1,2, Kathryn L Lunetta6,7,4, Emelia J Benjamin6,7,4,8,9, Patrick T Ellinor1,2,5. 1. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA. 2. Harvard Medical School, Boston, Massachusetts, USA. 3. Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany. 4. National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA. 5. Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA. 6. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA. 7. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. 8. Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 9. Cardiology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Abstract
BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia, and a recent genome-wide association study identified the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) as a novel AF susceptibility locus. HCN4 encodes for the cardiac pacemaker channel, and HCN4 mutations are associated with familial sinus bradycardia and AF. OBJECTIVE: The purpose of this study was to determine whether novel variants in the coding region of HCN4 contribute to the susceptibility for AF. METHODS: We sequenced the coding region of HCN4 for novel variants from 527 cases with early-onset AF from the Massachusetts General Hospital AF Study and 443 referents from the Framingham Heart Study. We used site-directed mutagenesis, cellular electrophysiology, immunocytochemistry, and confocal microscopy to functionally characterize novel variants. RESULTS: We found the frequency of novel coding HCN4 variants was 2-fold greater for individuals with AF (7 variants) compared to the referents (3 variants). We determined that of the 7 novel HCN4 variants in our AF cases, 1 (p.Pro257Ser, located in the amino-terminus adjacent to the first transmembrane spanning domain) did not traffic to cell membrane, whereas the remaining 6 were not functionally different from wild type. In addition, the 3 novel variants in our referents did not alter function compared to wild-type. Coexpression studies showed that the p.Pro257Ser mutant channel failed to colocalize with the wild-type HCN4 channel on the cell membrane. CONCLUSION: Our findings are consistent with HCN4 haploinsufficiency as the likely mechanism for early-onset AF in the p.Pro257Ser carrier.
BACKGROUND:Atrial fibrillation (AF) is the most common arrhythmia, and a recent genome-wide association study identified the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) as a novel AF susceptibility locus. HCN4 encodes for the cardiac pacemaker channel, and HCN4 mutations are associated with familial sinus bradycardia and AF. OBJECTIVE: The purpose of this study was to determine whether novel variants in the coding region of HCN4 contribute to the susceptibility for AF. METHODS: We sequenced the coding region of HCN4 for novel variants from 527 cases with early-onset AF from the Massachusetts General Hospital AF Study and 443 referents from the Framingham Heart Study. We used site-directed mutagenesis, cellular electrophysiology, immunocytochemistry, and confocal microscopy to functionally characterize novel variants. RESULTS: We found the frequency of novel coding HCN4 variants was 2-fold greater for individuals with AF (7 variants) compared to the referents (3 variants). We determined that of the 7 novel HCN4 variants in our AF cases, 1 (p.Pro257Ser, located in the amino-terminus adjacent to the first transmembrane spanning domain) did not traffic to cell membrane, whereas the remaining 6 were not functionally different from wild type. In addition, the 3 novel variants in our referents did not alter function compared to wild-type. Coexpression studies showed that the p.Pro257Ser mutant channel failed to colocalize with the wild-type HCN4 channel on the cell membrane. CONCLUSION: Our findings are consistent with HCN4 haploinsufficiency as the likely mechanism for early-onset AF in the p.Pro257Ser carrier.
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Authors: Ilja M Nolte; M Loretto Munoz; Vinicius Tragante; Azmeraw T Amare; Rick Jansen; Ahmad Vaez; Benedikt von der Heyde; Christy L Avery; Joshua C Bis; Bram Dierckx; Jenny van Dongen; Stephanie M Gogarten; Philippe Goyette; Jussi Hernesniemi; Ville Huikari; Shih-Jen Hwang; Deepali Jaju; Kathleen F Kerr; Alexander Kluttig; Bouwe P Krijthe; Jitender Kumar; Sander W van der Laan; Leo-Pekka Lyytikäinen; Adam X Maihofer; Arpi Minassian; Peter J van der Most; Martina Müller-Nurasyid; Michel Nivard; Erika Salvi; James D Stewart; Julian F Thayer; Niek Verweij; Andrew Wong; Delilah Zabaneh; Mohammad H Zafarmand; Abdel Abdellaoui; Sulayma Albarwani; Christine Albert; Alvaro Alonso; Foram Ashar; Juha Auvinen; Tomas Axelsson; Dewleen G Baker; Paul I W de Bakker; Matteo Barcella; Riad Bayoumi; Rob J Bieringa; Dorret Boomsma; Gabrielle Boucher; Annie R Britton; Ingrid Christophersen; Andrea Dietrich; George B Ehret; Patrick T Ellinor; Markku Eskola; Janine F Felix; John S Floras; Oscar H Franco; Peter Friberg; Maaike G J Gademan; Mark A Geyer; Vilmantas Giedraitis; Catharina A Hartman; Daiane Hemerich; Albert Hofman; Jouke-Jan Hottenga; Heikki Huikuri; Nina Hutri-Kähönen; Xavier Jouven; Juhani Junttila; Markus Juonala; Antti M Kiviniemi; Jan A Kors; Meena Kumari; Tatiana Kuznetsova; Cathy C Laurie; Joop D Lefrandt; Yong Li; Yun Li; Duanping Liao; Marian C Limacher; Henry J Lin; Cecilia M Lindgren; Steven A Lubitz; Anubha Mahajan; Barbara McKnight; Henriette Meyer Zu Schwabedissen; Yuri Milaneschi; Nina Mononen; Andrew P Morris; Mike A Nalls; Gerjan Navis; Melanie Neijts; Kjell Nikus; Kari E North; Daniel T O'Connor; Johan Ormel; Siegfried Perz; Annette Peters; Bruce M Psaty; Olli T Raitakari; Victoria B Risbrough; Moritz F Sinner; David Siscovick; Johannes H Smit; Nicholas L Smith; Elsayed Z Soliman; Nona Sotoodehnia; Jan A Staessen; Phyllis K Stein; Adrienne M Stilp; Katarzyna Stolarz-Skrzypek; Konstantin Strauch; Johan Sundström; Cees A Swenne; Ann-Christine Syvänen; Jean-Claude Tardif; Kent D Taylor; Alexander Teumer; Timothy A Thornton; Lesley E Tinker; André G Uitterlinden; Jessica van Setten; Andreas Voss; Melanie Waldenberger; Kirk C Wilhelmsen; Gonneke Willemsen; Quenna Wong; Zhu-Ming Zhang; Alan B Zonderman; Daniele Cusi; Michele K Evans; Halina K Greiser; Pim van der Harst; Mohammad Hassan; Erik Ingelsson; Marjo-Riitta Järvelin; Stefan Kääb; Mika Kähönen; Mika Kivimaki; Charles Kooperberg; Diana Kuh; Terho Lehtimäki; Lars Lind; Caroline M Nievergelt; Chris J O'Donnell; Albertine J Oldehinkel; Brenda Penninx; Alexander P Reiner; Harriëtte Riese; Arie M van Roon; John D Rioux; Jerome I Rotter; Tamar Sofer; Bruno H Stricker; Henning Tiemeier; Tanja G M Vrijkotte; Folkert W Asselbergs; Bianca J J M Brundel; Susan R Heckbert; Eric A Whitsel; Marcel den Hoed; Harold Snieder; Eco J C de Geus Journal: Nat Commun Date: 2017-06-14 Impact factor: 17.694