title: Three missense mutations in the protein C heavy chain causing type I and type II protein C deficiency.
abstract: We have studied the molecular basis of protein C deficiency in three families with a history of thromboembolic disease. An approximately 50% reduction in both functional and immunologic levels of protein C was detected in the plasma from two unrelated patients, designated protein C Osaka 1 and protein C Osaka 2. An approximately 50% reduction in functional level but normal immunologic level of protein C was detected in plasma from a third patient, designated protein C Osaka 3. DNA sequencing of the amplified DNA revealed one missense mutation in each case. Additional mutations in the coding sequence were excluded by DNA sequencing of all protein C exons. We identified a C-to-T change at nucleotide number 6,218 of the protein C gene in protein C Osaka 1. This results in the amino acid substitution of Arg-169 by Trp at the alpha-thrombin cleavage site. In protein C Osaka 2, a G-to-A change at nucleotide number 8,807 was identified leading to the amino acid substitution of Met-364 by Ile in the protease domain. This substitution may impair the synthesis or stability of protein C Osaka 2. In protein C Osaka 3, a G-to-C change at nucleotide number 8,868 was identified. This results in substitution of Gly-385 by Arg in the protease domain. Based on these, it was concluded that Arg-169-to-Trp mutation and Met-364-to-Ile mutation cause type I protein C deficiency and Gly-385-to-Arg mutation causes type II deficiency.
authors.affiliation: Laboratory of Thrombosis Research, National Cardiovascular Center Research Institute, Suita, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyata
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Zheng
authors.forename: T
authors.initials: T
authors.lastname: Sakata
authors.forename: N
authors.initials: N
authors.lastname: Tsushima
authors.forename: H
authors.initials: H
authors.lastname: Kato
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002965:Classification; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005796:Genes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011486:Protein C / Q000235:genetics*; D020151:Protein C Deficiency; D013923:Thromboembolism / Q000235:genetics
chemical_list: D011486:Protein C; C086830:protein C Osaka 1; C086831:protein C Osaka 2; C086832:protein C Osaka 3