title: The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects.
abstract: Heterozygosity for protein C deficiency is associated with thromboembolic episodes, but clinical symptoms are nonrandomly distributed among protein C deficient families. This finding has led to the provisional definition of clinically dominant and clinically recessive protein C deficiency. We report here the molecular basis of hereditary, clinically dominant protein C deficiency in a panel of 40 Dutch probands from apparently independent families. All but one subject was a heterozygote for a point mutation in the protein C gene. These 39 subjects shared 15 mutations, six of which occurred in more than one proband (between two and nine). The diversity in the 15 mutations, together with the observation that the most frequent Dutch mutation was also found in a Swedish family with clinically recessive protein C deficiency, makes it unlikely that the molecular basis of protein C deficiency will be different between the clinically dominant and recessive forms. The recurrence of one of the mutations is most likely due to a founder effect, which suggests that when an additional hereditary factor is involved in the clinical severity of protein C deficiency this factor may remain linked to the protein C gene over many generations.
authors.affiliation: Department of Hematology, University Medical Center Leiden, The Netherlands.
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
authors.forename: S R
authors.initials: SR
authors.lastname: Poort
authors.forename: C F
authors.initials: CF
authors.lastname: Allaart
authors.forename: E
authors.initials: E
authors.lastname: Briët
authors.forename: R M
authors.initials: RM
authors.lastname: Bertina
mesh_terms: D001483:Base Sequence; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009426:Netherlands; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011486:Protein C / Q000235:genetics; D020151:Protein C Deficiency
chemical_list: D011486:Protein C