title: Coding and non-coding variants in the SHOX2 gene in patients with early-onset atrial fibrillation.
abstract: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia with a strong genetic component. Molecular pathways involving the homeodomain transcription factor Shox2 control the development and function of the cardiac conduction system in mouse and zebrafish. Here we report the analysis of human SHOX2 as a potential susceptibility gene for early-onset AF. To identify causal variants and define the underlying mechanisms, results from 378 patients with early-onset AF before the age of 60 years were analyzed and compared to 1870 controls or reference datasets. We identified two missense mutations (p.G81E, p.H283Q), that were predicted as damaging. Transactivation studies using SHOX2 targets and phenotypic rescue experiments in zebrafish demonstrated that the p.H283Q mutation severely affects SHOX2 pacemaker function. We also demonstrate an association between a 3'UTR variant c.*28T>C of SHOX2 and AF (p = 0.00515). Patients carrying this variant present significantly longer PR intervals. Mechanistically, this variant creates a functional binding site for hsa-miR-92b-5p. Circulating hsa-miR-92b-5p plasma levels were significantly altered in AF patients carrying the 3'UTR variant (p = 0.0095). Finally, we demonstrate significantly reduced SHOX2 expression levels in right atrial appendages of AF patients compared to patients with sinus rhythm. Together, these results suggest a genetic contribution of SHOX2 in early-onset AF.
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University Heidelberg, INF 366, 69120, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hoffmann
authors.affiliation: Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partner site Munich, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Clauss
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Ina M
authors.initials: IM
authors.lastname: Berger
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University Heidelberg, INF 366, 69120, Heidelberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Weiß
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University Heidelberg, INF 366, 69120, Heidelberg, Germany.
authors.forename: Antonino
authors.initials: A
authors.lastname: Montalbano
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University Heidelberg, INF 366, 69120, Heidelberg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Röth
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University Heidelberg, INF 366, 69120, Heidelberg, Germany.
authors.forename: Madeline
authors.initials: M
authors.lastname: Bucher
authors.affiliation: Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Klier
authors.affiliation: Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partner site Munich, Munich, Germany.
authors.forename: Reza
authors.initials: R
authors.lastname: Wakili
authors.affiliation: Institut de génétique humaine (CNRS UPR 1142), Montpellier, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Seitz
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases, University Hospital Münster, Münster, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Heidelberg, Germany.|Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Flachsbart
authors.affiliation: Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.affiliation: Department of Cardiac Surgery, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany.
authors.forename: Sabina Pw
authors.initials: SP
authors.lastname: Guenther
authors.affiliation: Department of Cardiac Surgery, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Bagaev
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
authors.affiliation: Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partner site Munich, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.affiliation: Department of Human Molecular Genetics, Institute of Human Genetics, University Heidelberg, INF 366, 69120, Heidelberg, Germany. Gudrun.Rappold@med.uni-heidelberg.de.|DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Heidelberg, Germany. Gudrun.Rappold@med.uni-heidelberg.de.
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Rappold
mesh_terms: D000293:Adolescent; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D014162:Transfection; D055815:Young Adult; D015027:Zebrafish
chemical_list: D018398:Homeodomain Proteins; C484664:SHOX2 protein, human
keywords: Atrial fibrillation; Cardiac conduction system; MicroRNA; SHOX2; Transcription factor