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
Validation

Diseases presenting "heart disease" symptom

22q11.2 deletion syndrome

achondroplasia

acute rheumatic fever

adrenal incidentaloma

child syndrome

classical phenylketonuria

cohen syndrome

congenital diaphragmatic hernia

dentinogenesis imperfecta

esophageal adenocarcinoma

fabry disease

familial mediterranean fever

heparin-induced thrombocytopenia

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

kabuki syndrome

monosomy 21

omenn syndrome

phenylketonuria

sneddon syndrome

systemic capillary leak syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

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