The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency.
A Ser 460 to Pro mutation of protein S (PS), involving a T to C transition in exon XIII of the protein S alpha (PROS1) gene and known as the Heerlen polymorphism, was found in 16 of 85 symptomatic patients with PS deficiency (18.8%) and only 1 of 113 healthy subjects (0.8%). Another frequent polymorphism was described in exon XV of the PROS1 gene, in the codon for Pro 626 (CCA/CCG). We found that Heerlen polymorphism was associated with allele CCA and not with allele CCG, suggesting a probable transmission by a common ancestor. Most subjects bearing the Ser 460 to Pro mutation were deficient in free PS, but had normal total PS levels. Normal levels of the C4b-binding protein (C4b-BP) isoform containing a beta chain (C4b-BP beta +) ruled out increased C4b-BP beta + as a cause of the free-PS deficiency. The binding curves of the mutated (Heerlen) PS on C4b-BP immobilized on microplates were biphasic, suggesting that one molecule of C4b-BP can bind two molecules of Heerlen PS. Because normal PS binds to C4b-BP with 1:1 stoichiometry, this may explain the free-PS deficiency observed in patients carrying the Ser 460 to Pro mutation.
Duchemin
J
J
Unité INSERM 428, UFR des Sciences Pharmaceutiques et Biologiques, Université Paris V, France.
Gandrille
S
S
Borgel
D
D
Feurgard
P
P
Alhenc-Gelas
M
M
Matheron
C
C
Dreyfus
M
M
Dupuy
E
E
Juhan-Vague
I
I
Aiach
M
M
D002352:Carrier Proteins / Q000378:metabolism; D003062:Codon / Q000235:genetics; D003169:Complement Inactivator Proteins; D005260:Female; D005787:Gene Frequency; D005796:Genes; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins; D006801:Humans; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017293:Protein S / Q000235:genetics* / Q000378:metabolism; D018455:Protein S Deficiency / Q000235:genetics*; D013927:Thrombosis / Q000235:genetics
D002352:Carrier Proteins; D003062:Codon; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D017293:Protein S