title: A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation.
abstract: Holt-Oram syndrome (HOS) is a heart/hand syndrome clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome. Here, we describe a large atypical HOS family in which affected patients have mild skeletal deformations and paroxysmal atrial fibrillation, but few have congenital heart disease. Sequencing of TBX5 revealed a novel mutation, c.373G>A, resulting in the missense mutation p.Gly125Arg, in all investigated affected family members, cosegregating with the disease. We demonstrate that the mutation results in normal Nkx2-5 interaction, is correctly targeted to the nucleus, has significantly enhanced DNA binding and activation of both the Nppa(Anf) and Cx40 promoter, and significantly augments expression of Nppa, Cx40, Kcnj2, and Tbx3 in comparison with wild-type TBX5. Thus, contrary to previously published HOS mutations, the p.G125R TBX5 mutation results in a gain-of-function. We speculate that the gain-of-function mechanism underlies the mild skeletal phenotype and paroxysmal atrial fibrillation and suggest a possible role of TBX5 in the development of (paroxysmal) atrial fibrillation based on a gain-of-function either through a direct stimulation of target genes via TBX5 or indirectly via TBX5 stimulated TBX3. These findings may warrant a renewed look at the phenotypes of families and individuals hitherto not classified as HOS or as atypical but presenting with paroxysmal atrial fibrillation, because these may possibly be the result of additional TBX5 gain-of-function mutations.
authors.affiliation: Heart Failure Research Center, L2-108-1, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. a.v.postma@amc.uva.nl
authors.forename: Alex V
authors.initials: AV
authors.lastname: Postma
authors.forename: Judith B A
authors.initials: JB
authors.lastname: van de Meerakker
authors.forename: Inge B
authors.initials: IB
authors.lastname: Mathijssen
authors.forename: Phil
authors.initials: P
authors.lastname: Barnett
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
authors.forename: Aho
authors.initials: A
authors.lastname: Ilgun
authors.forename: Jan
authors.initials: J
authors.lastname: Lam
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Ronald H
authors.initials: RH
authors.lastname: Lekanne Deprez
authors.forename: Antoon F M
authors.initials: AF
authors.lastname: Moorman
mesh_terms: D000015:Abnormalities, Multiple; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics*; D001667:Binding, Competitive; D002478:Cells, Cultured; D002648:Child; D004247:DNA / Q000378:metabolism / Q000494:pharmacology; D004562:Electrocardiography; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D008040:Genetic Linkage; D005820:Genetic Testing; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D013577:Syndrome; D020825:T-Box Domain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D004247:DNA