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(Circulation Research. 2008;102:1433.)
© 2008 American Heart Association, Inc.

Clinical Research

A Gain-of-Function TBX5 Mutation Is Associated With Atypical Holt–Oram Syndrome and Paroxysmal Atrial Fibrillation

Alex V. Postma^*, Judith B.A. van de Meerakker^*, Inge B. Mathijssen, Phil Barnett, Vincent M. Christoffels, Aho Ilgun, Jan Lam, Arthur A.M. Wilde, Ronald H. Lekanne Deprez, Antoon F.M. Moorman

From the Heart Failure Research Center, Department of Anatomy & Embryology (A.V.P., J.B.A.v.d.M., P.B., V.M.C., A.I., A.F.M.M.), Clinical Genetics Department (I.B.M., R.H.L.D.), Paediatric Cardiology Department (J.L.), and Cardiology Department (A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.

Correspondence to A.V. Postma, Heart Failure Research Center, L2-108-1, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. E-mail a.v.postma{at}amc.uva.nl

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.

Key Words: atrial fibrillation • congenital heart defects • transcription factor • TBX5 • Holt–Oram syndrome

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Holt–Oram Syndrome and Atrial Fibrillation: Opening the (T)-Box

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