title: Homozygous deficiency of heparin cofactor II: relevance of P17 glutamate residue in serpins, relationship with conformational diseases, and role in thrombosis.
abstract: 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.
  
  
  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.
authors.affiliation: University of Murcia, Centro Regional de Hemodonación de Murcia, Murcia, Spain. javier.corral@carm.es
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: Justo
authors.initials: J
authors.lastname: Aznar
authors.forename: Rocio
authors.initials: R
authors.lastname: Gonzalez-Conejero
authors.forename: Piedad
authors.initials: P
authors.lastname: Villa
authors.forename: Antonia
authors.initials: A
authors.lastname: Miñano
authors.forename: Amparo
authors.initials: A
authors.lastname: Vayá
authors.forename: Robin W
authors.initials: RW
authors.lastname: Carrell
authors.forename: James A
authors.initials: JA
authors.lastname: Huntington
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
mesh_terms: D000328:Adult; D000990:Antithrombin III / Q000737:chemistry / Q000235:genetics; D020152:Antithrombin III Deficiency / Q000150:complications / Q000235:genetics; D018389:Codon, Nonsense; D018388:Codon, Terminator; D005260:Female; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000737:chemistry; D015844:Heparin Cofactor II / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000378:metabolism; D008958:Models, Molecular; D017354:Point Mutation; D011487:Protein Conformation; D011656:Pulmonary Emphysema / Q000209:etiology; D012008:Recurrence; D015843:Serpins / Q000097:blood / Q000737:chemistry; D019851:Thrombophilia / Q000150:complications / Q000235:genetics; D020246:Venous Thrombosis / Q000209:etiology; D000515:alpha 1-Antitrypsin / Q000032:analysis / Q000737:chemistry; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator; D015843:Serpins; D000515:alpha 1-Antitrypsin; D018698:Glutamic Acid; D015844:Heparin Cofactor II; D000990:Antithrombin III