A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease

Heterozygous Tbx5(del/+) mice were generated to study the mechanisms by whi ch TBX5 haploinsufficiency causes cardiac and forelimb abnormalities seen i n Holt-Oram syndrome. Tbx5 deficiency in homozygous mice (Tbx5(del/del)) de creased expression of multiple genes and caused severe hypoplasia of poster ior domains in the developing heart. Surprisingly, Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx 40) transcription, implicating these as Tbx5 target genes and providing a m echanism by which 50% reduction of T-box transcription factors cause diseas e. Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated. These studies provide one potential explanation for Holt-Oram syndrome con duction system defects, suggest mechanisms for intrafamilial phenotypic var iability, and account for related cardiac malformations caused by other tra nscription factor mutations.