The following is a summary of an article just published in the journal Cell (CELL 104:619-929, FEB 23, 2001):

“TBX1” is Responsible for Cardiovascular Defects in Velo-Cardio-Facial / Digeorge Syndrome


Velo-cardio-facial syndrome (VCFS)/DiGeorge syndrome (DGS) is a human disorder characterized by a large number of clinical features including cardiovascular defects. Most VCFS/DGS patients have a deletion of a region on one of their two copies of chromosome 22, termed 22q11.

To investigate the etiology of this disorder, we generated mice that have a deletion corresponding to that on 22q11. The mice had one normal copy of its chromosome and one copy harboring a small deletion. Approximately half of these mice died soon after birth, or around birth, and had cardiovascular defects. The mice also had a missing parathyroid gland, important for maintaining normal calcium levels. A gene therapy approach was used to return some of the genes that were deleted in the mice.

The cardiovascular defects in mice were partially rescued by adding back four human genes, including TBX1. These data allowed us to localize the gene(s) responsible for the cardiovascular defects. Mice overexpressing the four genes also had defects in structures affected in VCFS/DGS patients including the thymus gland. This suggested that the function of one of the four genes is very sensitive to altered gene copy number. Based upon its expression in the developing structures affected in patients with VCFS/DGS, we specifically inactivated one copy of Tbx1 in the mice. The resulting mice developed cardiovascular defects, and they were identical to those in the mice carrying the deletion and similar to those in VCFS/DGS patients.  (Click here for .pdf file )

These results, together with the expression patterns of Tbx1, suggest a major role for this gene in the molecular etiology of VCFS/DGS.

Sandra Merscher 1,*, Birgit Funke1,*, Jonathan A. Epstein2,* , Joerg Heyer1, Anne Puech3, Min Min Lu2, Ramnik J. Xavier4, Marie B. Demay5, Robert G. Russell6, Stephen Factor6, Kazuhito Tokooya7, Bruno St. Jore3, Melissa Lopez1, Raj K. Pandita1, Marie Lia 1, Danaise Carrion 1, Hubert Schorle8, , James B. Kobler9, Peter Scambler10, Anthony Wynshaw-Boris7, Arthur I. Skoultchi3, Bernice E. Morrow1 and Raju Kucherlapati1


*These three investigators contributed equally to this work.
1Department of Molecular Genetics,
2Cardiovascular Division, University of Pennsylvania, Philadelphia, PA 19104
3Department of Cell Biology,
4Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114
5Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114
6Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
7Department of Medicine, UCSD School of Medicine, La Jolla, CA 92093-0627
8Foschungszentrum Karlsruhe, Institut fuer Toxikologie und Genetik, Postfach 3640, 76133 Karlsruhe, Germany
9H. P. Mosher Laryngological Research Laboratory, Department of Otology and Laryngology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114
10Institute for Child Health, University of London College of Medicine, London, UK.

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