Mutation Triggers Crohn's Disease

Researchers have identified a mutation in a gene that may be responsible for the development of Crohn's disease, a chronic autoimmune digestive disorder.

Investigators at the Temple University School of Medicine (Philadelphia, PA, USA) identified a single point mutation at nucleotide 1586 that translated Ser511 to Asn511. They expressed these domains in Escherichia coli and found no differences in the rate of cleavage by purified kallikrein in the absence of N-glycosylation. However, when these domains were expressed in Chinese hamster ovary (CHO) cells, which are capable of glycosylation, an increased rate of cleavage of high molecular weight kininogen was observed. These findings were published in the October 15, 2003, issue of Blood.

Kininogen comprises a group of inactive plasma proteins that when proteolytically cleaved by kallikrein, a plasma protein of 110 kD molecular weight normally existing in plasma in a 1:1 complex with prekallikrein, give rise to kinins (bradykinin and kallidin). High molecular weight kininogen is split by plasma kallikrein to produce bradykinin. The complex is a cofactor in the activation of coagulation factor xii. The product of this reaction, xiia, in turn activates prekallikrein to kallikrein.

"Finding this mutation is important because we are now in a position to look for the same genetic mutations in humans, the presence of which would confirm that the protein kininogen plays an important role in the origin and development of Crohn's. We could then direct therapy toward modifying the effects of this protein,” explained senior author Dr. Robert Colman, professor of medicine at Temple University School of Medicine.




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