Gene that helps blood vessels form linked to complex birth defect

February 05, 2003

A gene known for its ability to form blood vessels has been found to be a key player in a chromosomal abnormality that causes potentially devastating birth defects in the heart and throughout the body.

In a study published in the February 2003 issue of Nature Medicine, a group of collaborators from across the globe reports that abnormalities in vascular endothelial growth factor, or VEGF, is a cause of DiGeorge syndrome. The syndrome can cause a wide range of heart defects, many of which are vascular in nature, as well as problems with the thymus and parathyroid gland, craniofacial abnormalities and mental retardation.

"We have found one of the downstream target genes," said Dr. Simon J. Conway, developmental biologist at the Medical College of Georgia and a senior author on the Nature Medicine paper along with Dr. Peter Carmeliet, director of The Center for Transgenic Technology at Katholieke Universiteit Leuven in Belgium. One next step would be to find why these VEGF defects occur with an ultimate goal of trying to prevent them, Dr. Conway said.

Researchers found this target "downstream" of human chromosome 22, which is known to be deleted in 60 to 70 percent of people with DiGeorge syndrome. Deletion of chromosome 22 removes a group of 24 genes as well, many of which are transcription genes known to control many downstream targets. Although the targets remain largely unknown, it's believed that these 24 genes control hundreds, maybe thousands, of downstream genes, which helps explain the complexity of the syndrome that can result when the chromosome is deleted, Dr. Conway said.

One of those 24 genes is Tbx1, which is widely considered the primary gene involved in DiGeorge syndrome, he said. In 2001, several research groups published their findings on mice models lacking Tbx1; those mice had some, but not all, the defects found in humans. In fact, although Tbx1 seems to have a role in DiGeorge and it may be the primary contributor to the heart defects that occur, no patient with DiGeorge syndrome has been found to have only a deletion of this gene.

That's one of the things that led scientists to look downstream of this master gene. Dr. Conway's lab, which focuses on normal and abnormal heart development, already was studying these downstream target genes, including VEGF.

"It struck us that in the mouse model for DiGeorge syndrome, a lot of the heart defects are vascular in nature, so we looked at one of the major, vascular genes, VEGF," he said. "If you knock out VEGF from a mouse model, it dies very, very early, before you get a heart, a head, even before you see an embryo proper."

Dr. Carmeliet in Belgium was the first to produce a knockout mouse in which VEGF was removed and replaced with the three most interesting of the five versions of the gene to try and determine the role of each. In the Nature Medicine study, researchers found that only one of the five versions, VEGF 164/164, was critical to DiGeorge; if it is absent or abnormal, the syndrome would occur. Both mice that had one of the other versions had the classic defects of DiGeorge syndrome. "That means if you change the contributions of the different types of VEGF and you don't have enough 164, you get what looks like DiGeorge syndrome in a mouse," Dr. Conway said. "It means it's a downstream target that is playing a role in DiGeorge." And it also means that one of the functions of the 24 genes deleted in DiGeorge is to ensure that the body has enough of VEGF 164/164, he said.

The researchers collected data in animal models, including the mouse and zebra fish - in collaboration with Mermaid Pharmaceuticals in Germany - then collaborated with other researchers, including those at the University of Pennsylvania School of Medicine, Albert Einstein College of Medicine and the Institute of Child Health in London, to examine human DNA from patients with DiGeorge.

They sequenced the human DNA to look for any abnormalities in the VEGF gene and found problems with the VEGF promoter, the piece of DNA that tells VEGF to be expressed and how to be expressed.

That means that people who have a deletion of chromosome 22 and problems with the VEGF promoter are at greatest risk of complex, congenital defects, Dr. Conway said. It also means that something on chromosome 22 is working with VEGF, and the researchers believe that's Tbx1, and that a reduction in Tbx1 and a corresponding reduction in VEGF are enough to produce DiGeorge.

"We have shown that we get all these defects and that there is an association with Tbx1," Dr. Conway said. "What we still don't know is why they occur. Our (next) job is to try and work out the cause."
-end-
Collaborators in Dr. Conway's lab included Dr. Jian Wang, graduate student Paige Kneer and research assistant Rhonda H. Rogers. The studies at MCG were funded in part by Dr. Conway's four grants from the National Institutes of Health and one from the American Heart Association.

Medical College of Georgia at Augusta University

Related Chromosome Articles from Brightsurf:

The bull Y chromosome has evolved to bully its way into gametes
In a new study, published Nov. 18 in the journal Genome Research, scientists in the lab of Whitehead Institute Member David Page present the first ever full, high-resolution sequence of the Y chromosome of a Hereford bull.

Evolution of the Y chromosome in great apes deciphered
New analysis of the DNA sequence of the male-specific Y chromosomes from all living species of the great ape family helps to clarify our understanding of how this enigmatic chromosome evolved.

The male Y chromosome does more than we thought
While the Y chromosome's role was believed to be limited to the functions of the sexual organs, an University of Montreal's scientist has shown that it impacts the functions of other organs as well.

The birth of a male sex chromosome in Atlantic herring
The evolution of sex chromosomes is of crucial importance in biology as it stabilises the mechanism underlying sex determination and usually results in an equal sex ratio.

Why the 'wimpy' Y chromosome hasn't evolved out of existence
The Y chromosome has shrunken drastically over 200 million years of evolution.

Novel insight into chromosome 21 and its effect on Down syndrome
A UCL-led research team has, for the first time, identified specific regions of chromosome 21, which cause memory and decision-making problems in mice with Down syndrome, a finding that provides valuable new insight into the condition in humans.

Breakthrough in sex-chromosome regulation
Researchers at Karolinska Institutet in Sweden have uncovered a chromosome-wide mechanism that keeps the gene expression of sex chromosomes in balance in our cells.

B chromosome first -- mechanisms behind the drive of B chromosomes uncovered
B chromosomes are supernumerary chromosomes, which often are preferentially inherited and showcase an increased transmission rate.

Unveiling disease-causing genetic changes in chromosome 17
Extensive single Watson-Crick base pair mutations can occur in addition to duplication or deletion of an entire group of genes on chromosomal region 17p11.2.

What causes rats without a Y chromosome to become male?
A look at the brains of an endangered spiny rat off the coast of Japan by University of Missouri (MU) Bond Life Sciences Center scientist Cheryl Rosenfeld could illuminate the subtle genetic influences that stimulate a mammal's cells to develop as male versus female in the absence of a Y chromosome.

Read More: Chromosome News and Chromosome Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.