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Heerlen polymorphism of protein S, an immunologic polymorphism due to
dimorphism of residue 460
RM Bertina, HK Ploos van Amstel, A van Wijngaarden, J Coenen, MP Leemhuis, PP Deutz-Terlouw, IK van der Linden and PH Reitsma
Department Hematology, University Hospital Leiden, The Netherlands.
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.
Volume 76,
Issue 3,
pp. 538-548,
08/01/1990
Copyright © 1990 by The American Society of Hematology
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