Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460

Autor: RM Bertina, HK Ploos van Amstel, A van Wijngaarden, J Coenen, MP Leemhuis, PP Deutz-Terlouw, IK van der Linden, PH Reitsma
Rok vydání: 1990
Předmět:
Zdroj: Blood. 76:538-548
ISSN: 1528-0020
0006-4971
Popis: We recently developed an enzyme-linked immunosorbent assay (ELISA) for total protein S (PS) antigen using the monoclonal antibody S-12. During the screening of thrombophilic patients we identified a patient, who was using marcoumar, with 0% PS by monoclonal ELISA and 23% PS by polyclonal ELISA. Further analysis of this patient and his family showed that the patient was a compound heterozygote for type 1 PS deficiency and for an abnormal PS molecule (PS-Heerlen) that was not recognized by the S-12 antibody. Similar observations were made in two sisters from an unrelated Dutch family. Subsequent studies showed that PS Heerlen has a slightly lower molecular weight (71,000) than normal PS (73,000), binds normally to C4b-binding protein, and retains full activated protein C cofactor activity. The alteration in the PS Heerlen molecule was identified as a substitution of Ser460 by Pro, which is due to a unique T---C transition in exon 13 of the active PS-alpha gene. The substitution occurs in the consensus sequence for the potential N-linked glycosylation of Asn458. Digestion with N-glycanase showed that normal PS probably contains three N-linked oligosaccharide side chains, while PS Heerlen contains only two (Asn458 not glycosylated?). Segregation analysis in the two original families showed that the presence of the genetic abnormality was always associated with the PS-Heerlen phenotype. The frequency of the PS- Heerlen allele was found to be 0.52% in the general population and 0.67% in a population of patients with unexplained thrombophilia. There is no evidence that the PS Heerlen allele is associated with an increased risk for thrombosis.
Databáze: OpenAIRE
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