1. Departments of Pediatrics (Cardiology) and
2. Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
3. University of Miami School of Medicine, 1600NW 10th Avenue, Miami, Florida 33136, USA
4. Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
5. Institute of Child Health, 30 Guilford Street, London WC1N UK
6. Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1S, UK
7. Howard Hughest Medical Institute, One Baylor Plaza, Houston, Texas 77030, USA

Correspondence to: Correspondence and requests for materials should be addressed to A.B. (e-mail: Email: baldini@bcm.tmc.edu).

Abstract

DiGeorge syndrome is characterized by cardiovascular, thymus and parathyroid defects and craniofacial anomalies, and is usually caused by a heterozygous 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 characteristic of the human disease². Here we have used a combination of chromosome engineering and P1 artificial chromosome transgenesis to localize the haploinsufficient 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 one copy of Tbx1 affects the development of the fourth pharyngeal arch arteries, whereas homozygous mutation severely disrupts the pharyngeal arch artery system. Our data show that haploinsufficiency of Tbx1 is sufficient to generate at least one important component of the DiGeorge syndrome phenotype in mice, and demonstrate the suitability of the mouse for the genetic dissection of microdeletion syndromes.