Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic archdefects in mice

DiGeorge syndrome is characterized by cardiovascular, thymus and parathyroi d defects and craniofacial anomalies, and is usually caused by a heterozygo us deletion of chromosomal region 22q11.2 (del22q11) (ref. 1). A targeted, heterozygous deletion, named Df(16)1, encompassing around 1 megabase of the homologous region in mouse causes cardiovascular abnormalities characteris tic of the human disease(2). Here we have used a combination of chromosome engineering and P1 artificial chromosome transgenesis to localize the haplo insufficient gene in the region, Tbx1. We show that Tbx1, a member of the T -box transcription factor family, is required for normal development of the pharyngeal arch arteries in a gene dosage-dependent manner. Deletion of on e copy of Tbx1 affects the development of the fourth pharyngeal arch arteri es, whereas homozygous mutation severely disrupts the pharyngeal arch arter y system. Our data show that haploinsufficiency of Tbx1 is sufficient to ge nerate at least one important component of the DiGeorge syndrome phenotype in mice, and demonstrate the suitability of the mouse for the genetic disse ction of microdeletion syndromes.