A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation.

[holt-oram syndrome]

Holt-Oram syndrome (HOS ) is a heart /hand syndrome clinically characterized by upper limb and cardiac malformations . Mutations in T -box transcription factor 5 (TBX 5 ) 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 TBX 5 revealed a novel mutation , c .373 G >A , resulting in the missense mutation p .Gly 125 Arg , in all investigated affected family members , cosegregating with the disease . We demonstrate that the mutation results in normal Nkx 2 -5 interaction , is correctly targeted to the nucleus , has significantly enhanced DNA binding and activation of both the Nppa (Anf ) and Cx 40 promoter , and significantly augments expression of Nppa , Cx 40 , Kcnj 2 , and Tbx 3 in comparison with wild-type TBX 5 . Thus , contrary to previously published HOS mutations , the p .G 125 R TBX 5 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 TBX 5 in the development of (paroxysmal ) atrial fibrillation based on a gain-of-function either through a direct stimulation of target genes via TBX 5 or indirectly via TBX 5 stimulated TBX 3 . 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 TBX 5 gain-of-function mutations .

Diseases
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Diseases presenting "affected family members, cosegregating with the disease" symptom

holt-oram syndrome

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