title: One novel and one recurrent mutation in the PROS1 gene cause type I protein S deficiency in patients with pulmonary embolism associated with deep vein thrombosis.
abstract: We investigated the molecular basis of type I protein S (PS) deficiency in two unrelated Japanese families, in which both probands developed pulmonary embolism associated with deep vein thrombosis. Nucleotide sequencing of amplified DNA revealed distinct point mutations in the PROS1 gene of the probands, which were designated protein S Sapporo 1 and protein S Sapporo 2. Additional mutations in the PROS1 gene were excluded by DNA sequencing of all exons and intron/exon boundaries. In the 25-year-old Japanese male patient who carried protein S Sapporo 1, we identified a heterozygous A-to-T change in the invariant ag dinucleotide of the acceptor splice site of intron f of the PROS1 gene. This mutation is a novel splice site mutation that impairs normal mRNA splicing, leading to exon 7 skipping, which was confirmed by platelet mRNA analysis. Translation of this mutant transcript would result in a truncated protein that lacks the entire epidermal growth factor-like domain 3 of the PS molecule. In a 31-year-old Japanese male and his younger brother who each carried protein S Sapporo 2, we detected a previously described heterozygous T-to-C transition at nucleotide position 1147 in exon 10 of the PROS1 gene, which predicts an amino acid substitution of tryptophan by arginine at residue 342 in the laminin G1 domain of the PS molecule. Both mutations would cause misfolding of the PS protein, resulting in the impairment of secretion, which is consistent with the type I PS deficiency phenotype.
authors.affiliation: Department of Orthodontics, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mizukami
authors.forename: Toru
authors.initials: T
authors.lastname: Nakabayashi
authors.forename: Sumiyoshi
authors.initials: S
authors.lastname: Naitoh
authors.forename: Mika
authors.initials: M
authors.lastname: Takeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Tarumi
authors.forename: Itaru
authors.initials: I
authors.lastname: Mizoguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ieko
authors.forename: Takao
authors.initials: T
authors.lastname: Koike
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001798:Blood Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D018076:DNA, Complementary / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D017293:Protein S; D018455:Protein S Deficiency / Q000097:blood / Q000235:genetics*; D011655:Pulmonary Embolism / Q000097:blood / Q000150:complications / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D017386:Sequence Homology, Amino Acid; D020246:Venous Thrombosis / Q000097:blood / Q000150:complications / Q000235:genetics*
chemical_list: D001798:Blood Proteins; D018076:DNA, Complementary; C523390:PROS1 protein, human; D017293:Protein S; D012333:RNA, Messenger