title: PROS1 analysis in 87 pedigrees with hereditary protein S deficiency demonstrates striking genotype-phenotype associations.
abstract: Hereditary protein S (PS) deficiency predisposes to venous thrombosis. Previously, we demonstrated a difference in risk of venous thrombosis between PS deficiency type I and type III. We used direct sequencing, multiplex ligation-dependent probe amplification (MLPA), and linkage analysis to study whether this difference could be explained by molecular heterogeneity. The study contained two sets of families with PS deficiency type I (cohort 1; 35 probands, 155 relatives) or type III (cohort 2; 52 probands, 241 relatives). In cohort 1, a mixed type I/type III PS-deficient phenotype was observed in 66% of the pedigrees. A total of 34 probands carried a mutant PROS1 allele, compared to one proband in cohort 2 (P<10(-10)). The proband's mutation was identified in all type I, but only in 57% of type III PS deficient relatives. MLPA-analysis in the mutation negative families did not reveal PROS1 deletions or insertions. Linkage analysis in 16 families showed cosegregation of PROS1 markers in the family with type I deficiency, but not in the 15 families with type III deficiency. The genotype-phenotype associations point to differences in genetic architecture. Whereas PS deficiency type I is a monogenic disease due to PROS1 allelic heterozygosity, PS deficiency type III is most likely a more complex or heterogeneous disorder.
authors.affiliation: Department of Haematology, Division of Haemostasis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Min Ki
authors.initials: MK
authors.lastname: Ten Kate
authors.forename: Mathieu
authors.initials: M
authors.lastname: Platteel
authors.forename: Rene
authors.initials: R
authors.lastname: Mulder
authors.forename: Peter
authors.initials: P
authors.lastname: Terpstra
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
authors.forename: Pieter H
authors.initials: PH
authors.lastname: Reitsma
authors.forename: Gerrit
authors.initials: G
authors.lastname: van der Steege
authors.forename: Jan
authors.initials: J
authors.lastname: van der Meer
mesh_terms: D000328:Adult; D000368:Aged; D001798:Blood Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017293:Protein S; D018455:Protein S Deficiency / Q000150:complications / Q000235:genetics*; D020246:Venous Thrombosis / Q000235:genetics
chemical_list: D001798:Blood Proteins; C523390:PROS1 protein, human; D017293:Protein S