{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:19:32Z","timestamp":1789373972521,"version":"build-2803163510"},"reference-count":52,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":3425,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Summary<\/jats:title><jats:p>Atrial fibrillation (AF) is the most common cardiac arrhythmia and carries a significant risk of stroke and heart failure. The molecular etiologies of AF are poorly understood, leaving patients with limited therapeutic options. AF has been recognized as an inherited disease in almost 30% of patient cases. However, few genetic loci have been identified and the mechanisms linking genetic variants to AF susceptibility remain unclear. By sequencing 193 probands with lone AF, we identified a Q76E variant within the coding sequence of the bone morphogenetic protein (BMP) antagonist gremlin-2 (GREM2) that increases its inhibitory activity. Functional modeling in zebrafish revealed that, through regulation of BMP signaling, GREM2 is required for cardiac laterality and atrial differentiation during embryonic development. GREM2 overactivity results in slower cardiac contraction rates in zebrafish, and induction of previously identified AF candidate genes encoding connexin-40, sarcolipin and atrial natriuretic peptide in differentiated mouse embryonic stem cells. By live heart imaging in zebrafish overexpressing wild-type or variant GREM2, we found abnormal contraction velocity specifically in atrial cardiomyocytes. These results implicate, for the first time, regulators of BMP signaling in human AF, providing mechanistic insights into the pathogenesis of the disease and identifying potential new therapeutic targets.<\/jats:p>","DOI":"10.1242\/dmm.010488","type":"journal-article","created":{"date-parts":[[2012,12,8]],"date-time":"2012-12-08T07:16:15Z","timestamp":1354950975000},"source":"Crossref","is-referenced-by-count":27,"title":["Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene<i>GREM2<\/i>regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm"],"prefix":"10.1242","author":[{"given":"Iris I.","family":"M\u00fcller","sequence":"first","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, TN 37232, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Melville","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, TN 37232, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vineeta","family":"Tanwar","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Witold M.","family":"Rybski","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, TN 37232, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin M.","family":"Shoemaker","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Der","family":"Wang","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, TN 37232, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Schoenhard","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan M.","family":"Roden","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawood","family":"Darbar","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ela W.","family":"Knapik","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, TN 37232, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonis K.","family":"Hatzopoulos","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2012,1,1]]},"reference":[{"key":"2021042513075330500_b1-0060332","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.yjmcc.2009.07.020","article-title":"Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation","volume":"48","author":"Abraham","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2021042513075330500_b2-0060332","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1161\/CIRCULATIONAHA.106.668392","article-title":"Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death","volume":"115","author":"Antzelevitch","year":"2007","journal-title":"Circulation"},{"key":"2021042513075330500_b3-0060332","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1210\/me.2003-0227","article-title":"Comparative genomic analysis of the eight-membered ring cystine knot-containing bone morphogenetic protein antagonists","volume":"18","author":"Avsian-Kretchmer","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"2021042513075330500_b4-0060332","doi-asserted-by":"crossref","first-page":"77","DOI":"10.2353\/ajpath.2008.070648","article-title":"Egr-1 regulates expression of the glial scar component phosphacan in astrocytes after experimental stroke","volume":"173","author":"Beck","year":"2008","journal-title":"Am. J. Pathol."},{"key":"2021042513075330500_b5-0060332","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1242\/dev.126.14.3253","article-title":"Regulation of midline development by antagonism of lefty and nodal signaling","volume":"126","author":"Bisgrove","year":"1999","journal-title":"Development"},{"key":"2021042513075330500_b6-0060332","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.ydbio.2007.03.001","article-title":"Zebrafish Bmp4 regulates left-right asymmetry at two distinct developmental time points","volume":"305","author":"Chocron","year":"2007","journal-title":"Dev. Biol."},{"key":"2021042513075330500_b7-0060332","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nmeth.1974","article-title":"The 1000 Genomes Project: data management and community access","volume":"9","author":"Clarke","year":"2012","journal-title":"Nat. Methods"},{"key":"2021042513075330500_b8-0060332","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.hrthm.2007.09.002","article-title":"Genetics of atrial fibrillation: rare mutations, common polymorphisms, and clinical relevance","volume":"5","author":"Darbar","year":"2008","journal-title":"Heart Rhythm"},{"key":"2021042513075330500_b9-0060332","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.hrthm.2007.02.006","article-title":"Polymorphism modulates symptomatic response to antiarrhythmic drug therapy in patients with lone atrial fibrillation","volume":"4","author":"Darbar","year":"2007","journal-title":"Heart Rhythm"},{"key":"2021042513075330500_b10-0060332","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.jacc.2011.12.010","article-title":"Repolarization recipes for atrial fibrillation: beyond single channel variants","volume":"59","author":"Darbar","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"2021042513075330500_b11-0060332","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/ng.537","article-title":"Common variants in KCNN3 are associated with lone atrial fibrillation","volume":"42","author":"Ellinor","year":"2010","journal-title":"Nat. Genet."},{"key":"2021042513075330500_b12-0060332","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/ng.2261","article-title":"Meta-analysis identifies six new susceptibility loci for atrial fibrillation","volume":"44","author":"Ellinor","year":"2012","journal-title":"Nat. Genet."},{"key":"2021042513075330500_b13-0060332","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1242\/dev.127.5.1081","article-title":"Mesendoderm and left-right brain, heart and gut development are differentially regulated by pitx2 isoforms","volume":"127","author":"Essner","year":"2000","journal-title":"Development"},{"key":"2021042513075330500_b14-0060332","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1001\/archinte.1995.00430050045005","article-title":"Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications","volume":"155","author":"Feinberg","year":"1995","journal-title":"Arch. Intern. Med."},{"key":"2021042513075330500_b15-0060332","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1161\/01.RES.0000141134.64811.0a","article-title":"Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation","volume":"95","author":"Firouzi","year":"2004","journal-title":"Circ. Res."},{"key":"2021042513075330500_b16-0060332","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1101\/gad.1682108","article-title":"BMP\/SMAD1 signaling sets a threshold for the left\/right pathway in lateral plate mesoderm and limits availability of SMAD4","volume":"22","author":"Furtado","year":"2008","journal-title":"Genes Dev"},{"key":"2021042513075330500_b17-0060332","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1056\/NEJMoa052800","article-title":"Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation","volume":"354","author":"Gollob","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"2021042513075330500_b18-0060332","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nature06007","article-title":"Variants conferring risk of atrial fibrillation on chromosome 4q25","volume":"448","author":"Gudbjartsson","year":"2007","journal-title":"Nature"},{"key":"2021042513075330500_b19-0060332","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1038\/ng.417","article-title":"A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke","volume":"41","author":"Gudbjartsson","year":"2009","journal-title":"Nat. Genet."},{"key":"2021042513075330500_b20-0060332","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1056\/NEJM199809033391003","article-title":"Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins","volume":"339","author":"Ha\u00efssaguerre","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"2021042513075330500_b21-0060332","doi-asserted-by":"crossref","first-page":"e2904","DOI":"10.1371\/journal.pone.0002904","article-title":"Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells","volume":"3","author":"Hao","year":"2008","journal-title":"PLoS ONE"},{"key":"2021042513075330500_b22-0060332","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1056\/NEJMoa0706300","article-title":"Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation","volume":"359","author":"Hodgson-Zingman","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"2021042513075330500_b23-0060332","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1161\/CIRCGENETICS.110.958058","article-title":"PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression","volume":"4","author":"Kirchhof","year":"2011","journal-title":"Circ. Cardiovasc. Genet."},{"key":"2021042513075330500_b24-0060332","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.ydbio.2009.10.013","article-title":"PRDC regulates placode neurogenesis in chick by modulating BMP signalling","volume":"336","author":"Kriebitz","year":"2009","journal-title":"Dev. Biol."},{"key":"2021042513075330500_b25-0060332","first-page":"3420","article-title":"Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers","volume":"119","author":"Levin","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2021042513075330500_b26-0060332","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2021042513075330500_b27-0060332","doi-asserted-by":"crossref","first-page":"5081","DOI":"10.1242\/dev.129.21.5081","article-title":"Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into atrioventricular cushions","volume":"129","author":"Liu","year":"2002","journal-title":"Development"},{"key":"2021042513075330500_b28-0060332","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.hfc.2009.12.004","article-title":"Genetics of atrial fibrillation","volume":"6","author":"Lubitz","year":"2010","journal-title":"Heart Fail. Clin."},{"key":"2021042513075330500_b29-0060332","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1242\/dmm.007625","article-title":"The feelgood mutation in zebrafish dysregulates COPII-dependent secretion of select extracellular matrix proteins in skeletal morphogenesis","volume":"4","author":"Melville","year":"2011","journal-title":"Dis. Model. Mech."},{"key":"2021042513075330500_b30-0060332","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nature09708","article-title":"Mapping copy number variation by population-scale genome sequencing","volume":"470","author":"Mills","year":"2011","journal-title":"Nature"},{"key":"2021042513075330500_b31-0060332","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1161\/CIRCULATIONAHA.105.595140","article-title":"Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence","volume":"114","author":"Miyasaka","year":"2006","journal-title":"Circulation"},{"key":"2021042513075330500_b32-0060332","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1161\/CIRCRESAHA.107.161182","article-title":"Pitx2c and Nkx2-5 are required for the formation and identity of the pulmonary myocardium","volume":"101","author":"Mommersteeg","year":"2007","journal-title":"Circ. Res."},{"key":"2021042513075330500_b33-0060332","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1016\/j.hrthm.2009.07.011","article-title":"Atrial fibrillation: a developmental point of view","volume":"6","author":"Mommersteeg","year":"2009","journal-title":"Heart Rhythm"},{"key":"2021042513075330500_b34-0060332","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ydbio.2007.11.038","article-title":"Two novel type II receptors mediate BMP signalling and are required to establish left-right asymmetry in zebrafish","volume":"315","author":"Monteiro","year":"2008","journal-title":"Dev. Biol."},{"key":"2021042513075330500_b35-0060332","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1002\/dvdy.20925","article-title":"Expression of the protein related to Dan and Cerberus gene \u2013 prdc \u2013 during eye, pharyngeal arch, somite, and swim bladder development in zebrafish","volume":"235","author":"M\u00fcller","year":"2006","journal-title":"Dev. Dyn."},{"key":"2021042513075330500_b36-0060332","first-page":"675","article-title":"Lone AF - etiologic factors and genetic insights into pathophysiolgy","volume":"1","author":"Parvez","year":"2010","journal-title":"J. Atr. Fibrillation"},{"key":"2021042513075330500_b37-0060332","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1006\/dbio.1999.9240","article-title":"A mouse cerberus\/Dan-related gene family","volume":"209","author":"Pearce","year":"1999","journal-title":"Dev. Biol."},{"key":"2021042513075330500_b38-0060332","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera \u2013 a visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"2021042513075330500_b39-0060332","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1089\/scd.2011.0326","article-title":"Continuous antagonism by Dkk1 counter activates canonical Wnt signaling and promotes cardiomyocyte differentiation of embryonic stem cells","volume":"21","author":"Rai","year":"2012","journal-title":"Stem Cells Dev"},{"key":"2021042513075330500_b40-0060332","doi-asserted-by":"crossref","first-page":"2983","DOI":"10.1101\/gad.13.22.2983","article-title":"Gata5 is required for the development of the heart and endoderm in zebrafish","volume":"13","author":"Reiter","year":"1999","journal-title":"Genes Dev"},{"key":"2021042513075330500_b41-0060332","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20100305","article-title":"Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists","volume":"429","author":"Rider","year":"2010","journal-title":"Biochem. J."},{"key":"2021042513075330500_b42-0060332","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/j.jacc.2012.04.030","article-title":"Chromosome 4q25 variants are genetic modifiers of latent familial atrial fibrillation","volume":"60","author":"Ritchie","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"2021042513075330500_b43-0060332","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/29004","article-title":"Pitx2 determines left-right asymmetry of internal organs in vertebrates","volume":"394","author":"Ryan","year":"1998","journal-title":"Nature"},{"key":"2021042513075330500_b44-0060332","doi-asserted-by":"crossref","first-page":"e10367","DOI":"10.1371\/journal.pone.0010367","article-title":"Sec24D-dependent transport of extracellular matrix proteins is required for zebrafish skeletal morphogenesis","volume":"5","author":"Sarmah","year":"2010","journal-title":"PLoS ONE"},{"key":"2021042513075330500_b45-0060332","doi-asserted-by":"crossref","first-page":"3421","DOI":"10.1242\/dev.129.14.3421","article-title":"BMP2 is a positive regulator of Nodal signaling during left-right axis formation in the chicken embryo","volume":"129","author":"Schlange","year":"2002","journal-title":"Development"},{"key":"2021042513075330500_b46-0060332","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1101\/gad.11.4.451","article-title":"A role for bone morphogenetic proteins in the induction of cardiac myogenesis","volume":"11","author":"Schultheiss","year":"1997","journal-title":"Genes Dev"},{"key":"2021042513075330500_b47-0060332","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.bbrc.2011.05.113","article-title":"Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation","volume":"410","author":"Shanmugam","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021042513075330500_b48-0060332","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0002-9343(02)01236-6","article-title":"A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew\/Paisley study","volume":"113","author":"Stewart","year":"2002","journal-title":"Am. J. Med."},{"key":"2021042513075330500_b49-0060332","doi-asserted-by":"crossref","first-page":"23134","DOI":"10.1074\/jbc.M402376200","article-title":"Protein related to DAN and cerberus is a bone morphogenetic protein antagonist that participates in ovarian paracrine regulation","volume":"279","author":"Sudo","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021042513075330500_b50-0060332","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ydbio.2011.09.019","article-title":"Tfap2a and Foxd3 regulate early steps in the development of the neural crest progenitor population","volume":"360","author":"Wang","year":"2011","journal-title":"Dev. Biol."},{"key":"2021042513075330500_b51-0060332","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nature05911","article-title":"Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls","volume":"447","author":"Wellcome Trust Case Control Consortium","year":"2007","journal-title":"Nature"},{"key":"2021042513075330500_b52-0060332","doi-asserted-by":"crossref","first-page":"5147","DOI":"10.1242\/dev.067785","article-title":"Gremlin 2 regulates distinct roles of BMP and Endothelin 1 signaling in dorsoventral patterning of the facial skeleton","volume":"138","author":"Zuniga","year":"2011","journal-title":"Development"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/6\/2\/332\/1864989\/332.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.010488\/2032443\/dmm_010488.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.010488\/2032443\/dmm_010488.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T20:36:55Z","timestamp":1643834215000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.010488\/261923\/Functional-modeling-in-zebrafish-demonstrates-that"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,1,1]]},"references-count":52,"URL":"https:\/\/doi.org\/10.1242\/dmm.010488","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2012,1,1]]},"article-number":"dmm.010488"}}