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

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 I 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-α 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.