Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with de novo hemizygous 22q11.2 deletions and is characterized by malformations attributed to abnormal development of the pharyngeal arches and pouches. The main physical findings include aortic arch and outflow tract heart defects, thymus gland hypoplasia or aplasia and craniofacial anomalies. The disorder varies greatly in expressivity; while some patients are mildly affected with learning disabilities and subtle craniofacial malformations, others die soon after birth with major cardiovascular defects and thymus gland aplasia. In addition to the main clinical features, many other findings are associated with the disorder such as chronic otitis media and hypocalcemia. Tbx1, a gene encoding a T-box transcription factor, which is hemizygously deleted on chromosome 22q11.2, was found to be a strong candidate for the equivalent of human VCFS/DGS in mice. Mice hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes had severe malformations in the affected structures; neither precisely modeling the syndrome. Interestingly, bacterial artificial chromosome (BAC) transgenic mice overexpressing human TBX1 and three other transgenes, had similar malformations as VCFS/DGS patients. By employing genetic complementation studies, we demonstrate that altered TBX1 dosage and not overexpression of the other transgenes is responsible for most of the defects in the BAC transgenic mice. Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a Tbx1 dose dependent manner, thus providing a molecular basis for the pathogenesis and varied expressivity of the syndrome.