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Big-hearted fish reveals genetics of cardiovascular condition
Date:2/25/2009

PHILADELPHIA Researchers at the University of Pennsylvania School of Medicine have unlocked the mystery of a puzzling human disease and gained insight into cardiovascular development, all thanks to a big-hearted fish.

Mark Kahn, MD, Associate Professor of Medicine, graduate student Benjamin Kleaveland, and colleagues report in the February issue of Nature Medicine that a human vascular condition called Cerebral Cavernous Malformation (CCM) is caused by leaky junctions between cells in the lining of blood vessels. By combining studies with zebrafish and mice, the researchers found that the aberrant junctions are the result of mutated or missing proteins in a novel biochemical process, the so-called Heart-of-glass (HEG)-CCM pathway.

The HEG-CCM pathway "is essential to regulate endothelial cell-cell interaction, both during the time that vertebrates make the cardiovascular system and later in life," says Kahn. "Its loss later in life confers this previously unexplained disease, cerebral cavernous malformation."

CCM proteins, along with the receptor HEG, are responsible for building properly formed blood and lymphatic vessels during embryonic development by sealing the cell-cell junctions in the walls of vessels; loss of any of these proteins disrupts those seals, causing leaky vasculature.

Cerebral Cavernous Malformations are abnormal clusters of leaky blood vessels, typically in the brain, which can cause both seizures and strokes. The condition affects about 1 in 1,000 people, about 20% of whom carry a genetic predisposition for the condition. Researchers had already identified the genes responsible for the disease indeed they were named CCM1, CCM2, and CCM3, in recognition of that fact but not what those genes did.

That's where the big-hearted fish come in. Several years ago, another research team discovered that mutations in CCM1, CCM2, or HEG (which had not previously been linked to CCM) caused zebr
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Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania School of Medicine
Source:Eurekalert  

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