February 2001

From University of Pennsylvania Medical Center

Penn cardiologist reports success in search of gene

Responsible for cardiovascular defects in DiGeorge Syndrome

(Philadelphia, PA) – Imagine having to discover the guiltiest of 24 suspects, each one responsible for a unknown crime in their own right, and you will have an appreciation for the task undertaken by researchers at the University of Pennsylvania Medical Center and the Albert Einstein College of Medicine. DiGeorge Syndrome is known for a variety of congenital problems, and affects one in every 4000 live births. But most notably it is known for causing cardiovascular defects, indeed, the disorder is the second leading cause of heart disease in children.

The researchers unmask the DiGeorge Syndrome culprit responsible for heart defects in the February 23 edition of the journal Cell. The gene, Tbx1, normally functions in the development of blood vessels near the heart. Its discovery paves the way for prenatal testing for the defect and better preparation for the effects of the DiGeorge Syndrome at birth.

"Oftentimes a syndrome is a catchall term for a host of separate, yet related, problems," said Jonathan Epstein, MD, Assistant Professor of Cardiology and co-author of the Cell paper. "Up until now, we have only known that the syndrome can be caused by the loss of a small portion of a particular chromosome, the so-called DiGeorge region. Now we think we have finally identified the critical gene in that region."

Chromosomes are individual bunches of DNA, and serve as the means by which genes are passed on from parent to child. Most ‘normally’ developed people have two copies of every chromosome, 46 in all – 23 from each parent. Researchers have known for some time that DiGeorge sufferers have typically lost a portion of Chromosome 22, but it was not until recently that the chromosome was deciphered in the Human Genome Project. A total of 24 genes in the lost portion became suspect, but researchers were not sure the role of any of them in a developing fetus.

"The effects of genes like Tbx1 are dose dependent," said Epstein, "and if a fetus only receives one working copy of the gene, it might not be enough to let it develop normally."

Without two working copies of the gene, the blood vessels surrounding the developing heart do not form correctly, often leading to problems – and necessitating surgery – at birth. While one copy of the gene is enough to start the work, it is not enough to do the job right. The defects manifest themselves in various ways, but most of the errors seem to be in how the blood vessels connect to each other as the fetus grows. Often these defects do not pose a problem to the fetus, but become readily apparent at birth. In some cases, these vessels can even form a ‘vascular ring’ around the trachea, slowly choking off air from the lungs or resulting in what is commonly called a ‘blue baby.’ Tbx1 is also a member of a family of dosage-dependent genes, with closely related genes implicated in other disorders, such as Holt-Oram Syndrome, that are also associated with heart defects.

One of the major stumbling points to studies of this type is to find an appropriate animal model. Fortunately for the researchers, genes comparable to the human Chromosome 22 also exist on mouse Chromosome 16. To determine that Tbx1 was the heart defect gene in DiGeorge Syndrome, the researchers worked backwards – starting with mice that lacked the DiGeorge region and breeding in genes in groups of four. Epstein provided the cardiology expertise to determine what adding genes did to the fetal mouse heart and surrounding tissue. "When we came to the mice with a working set of Tbx1, it became quite apparent that we had caught the right gene," said Epstein. "This work will pave the way for confirming the importance of Tbx1 in humans with congenital heart disease."

By identifying the DiGeorge gene for heart disease, it may now be possible to screen for the gene in people with a family history of congenital heart disease.

"Sometimes early detection can make a tremendous difference in the survival and quality of life of children that suffer from congenital heart defects," said Michael Parmacek, MD, Chief of the Cardiovascular Division of the Penn School of Medicine. "It also opens the door for treatment at birth or even new surgical techniques such as those that have been developed for patients still in the womb."

Esptein’s research is supported by grants from the National Institutes on Health, the W.W. Smith Charitable Trust, and the American Heart Association.

Graphics available by request.












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