title: Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene GREM2 regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm.
abstract: 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.
authors.affiliation: Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Iris I
authors.initials: II
authors.lastname: Müller
authors.forename: David B
authors.initials: DB
authors.lastname: Melville
authors.forename: Vineeta
authors.initials: V
authors.lastname: Tanwar
authors.forename: Witold M
authors.initials: WM
authors.lastname: Rybski
authors.forename: Amrita
authors.initials: A
authors.lastname: Mukherjee
authors.forename: M Benjamin
authors.initials: MB
authors.lastname: Shoemaker
authors.forename: Wan-Der
authors.initials: WD
authors.lastname: Wang
authors.forename: John A
authors.initials: JA
authors.lastname: Schoenhard
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Dawood
authors.initials: D
authors.lastname: Darbar
authors.forename: Ela W
authors.initials: EW
authors.lastname: Knapik
authors.forename: Antonis K
authors.initials: AK
authors.lastname: Hatzopoulos
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D016207:Cytokines; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006325:Heart Atria / Q000196:embryology / Q000473:pathology / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D038081:Organogenesis / Q000235:genetics; D010375:Pedigree; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D016207:Cytokines; C495107:GREM2 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D029961:Zebrafish Proteins; C516331:grem2b protein, zebrafish