Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Corral, J. et al.

Corral, Aznar, Gonzalez-Conejero, Villa, Miñano, Vayá, Carrell, Huntington, Vicente,

Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis.

BACKGROUND: Heparin cofactor II (HCII) is a hepatic serpin with significant antithrombin activity that has been implicated in coagulation, inflammation, atherosclerosis, and wound repair. Recent data obtained in mice lacking HCII suggest that this serpin might inhibit thrombosis in the arterial circulation. However, the clinical relevance and molecular mechanisms associated with deficiency of HCII in humans are unclear. METHODS AND RESULTS: We studied the first family with homozygous HCII deficiency, identifying a Glu428Lys mutation affecting a conserved glutamate at the hinge (P17) of the reactive loop. No carrier reported arterial thrombosis, and only 1 homozygous HCII-deficient patient developed severe deep venous thrombosis, but she also had a de novo Glu100Stop nonsense truncation in the antithrombin gene. CONCLUSIONS: Our results confirm the key structural role of the P17 glutamate in serpins. The same mutation causes conformational instability and polymerization in 3 serpins: Drosophila necrotic, human alpha1-antitrypsin, and human HCII, which explains their plasma deficiency. In the family under study here, however, plasma HCII deficiency was not associated with a significant clinical phenotype.[1]

References

Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis. Corral, J., Aznar, J., Gonzalez-Conejero, R., Villa, P., Miñano, A., Vayá, A., Carrell, R.W., Huntington, J.A., Vicente, V. Circulation (2004) [Pubmed]

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