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

Abstract

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.373GϾA, 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 Ⅲ congenital heart defects Ⅲ transcription factor Ⅲ TBX5 Ⅲ Holt-Oram syndrome C ongenital heart defects are among the most common congenital defects in children, occurring in 1% to 2% of live births and in Ϸ5% of stillbirths. 1 Congenital heart defects can either appear as a spontaneous defect or as part of a syndrome. One such syndrome is the Holt-Oram Syndrome (HOS) (Online Mendelian Inheritance in Man [OMIM] no. 142900), 2 appearing in 1 of 100 000 live births 3 and segregating in an autosomal dominant fashion. It is characterized by bilateral forelimb deformities and congenital heart defects. Clinically, there are 3 variations of HOS: affected individuals may have only skeletal anomalies (27.4%), only cardiac defects (3.9%), or both (68.7%). 4 The limb and heart malformations can vary from mild to severe, even within families, and no correlation exists between the severity of the cardiac and skeletal abnormalities of the patient. 5 The congenital heart malformations are generally secundum atrial septal defects (ASD II) or ventricular septal defects, but others, such as mitral valve defects and cardiac conduction defects, most notably atrioventricular block, have also been reported. 3,6 Single-gene mutations were identified in the T-box transcription factor 5 (TBX5) in multiple HOS patients. 7 TBX5 is a member of the T-box transcription factor family that regulates a wide variety of developmental processes in ...

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