Loss of gene involved in clot formation may explain bleeding disorder, LAD-III
Patients with the syndrome leukocyte adhesion deficiency (LAD) III suffer from recurrent infections and an increased tendency to bleed. The exact defect responsible for this disease remains unclear. In a study appearing online on May 10 in advance of publication in the June print issue of the Journal of Clinical Investigation, Denisa Wagner and colleagues from Harvard Medical School show that mice engineered to lack the gene CalDAG-GEFI have a combination of defects in their leukocytes and platelets, similar to those observed in LAD-III patients.
In response to injury of the blood vessel lining, blood platelets adhere to fibrin, endothelial cells lining the vessel wall, and to each other via adhesion receptors known as integrins, to form what is often referred to as a blood clot. Wagner and colleagues evaluated the role of CalDAG-GEFI in integrin activation. They observed significant defects in beta1- and beta2-integrinmediated adhesion of CalDAG-GEFIdeficient neutrophils, which impaired the response of these cells to injury and inflammation. In addition, they found that CalDAG-GEFI was essential for the activation of beta1 integrins on the surface of platelets and that CalDAG-GEFI-/- mice were unable to form blood clots. The data indicate that CalDEG-GEFI regulates beta integrin function and suggests that this gene may be defective in patients with LAD-III.
TITLE: Mick lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III
CBR Institute for Biomedical Research and Harvard Medical School, Boston, Massachusetts, USA.
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