Recent VCFS Discovery


Velo-Cardio-Facial Syndrome
Educational Foundation, Inc.

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

*These three investigators contributed equally to this
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
10Institute for Child Health, University of London
College of Medicine, London, UK.

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Last modified: 09/07/05