title: Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension.
abstract: Prostacyclin inhibits platelet aggregation, smooth muscle cell proliferation, and vasoconstriction. The prostacyclin synthase (PGIS) gene is a candidate gene for cardiovascular disease. The purpose of this study was to locate possible mutations in the PGIS gene related to hypertension and cerebral infarction. Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we discovered a T to C transition at the +2 position of the splicing donor site of intron 9 in patients with essential hypertension (EH). In vitro expression analysis of an allelic minigene consisting of exons 8-10 revealed that the nucleotide transition causes skipping of exon 9. This in turn alters the translational reading frame of exon 10 and introduces a premature stop codon (TGA). A three-dimensional model shows that the splice site mutation produces a truncated protein with a deletion in the heme-binding region. This splice site mutation was found in only one subject in 200 EH patients and 200 healthy controls. Analysis of the patient's family members revealed the mutation in two of the three siblings. The urinary excretion of prostacyclin metabolites in subjects with the mutation was significantly decreased. All subjects displaying the splice site mutation in the PGIS gene were hypertensive. In this study, we report a novel splicing mutation in the PGIS gene, which is associated with hypertension in a family. It is thought that this mechanism may involve in the pathophysiology of their hypertension.
authors.affiliation: Division of Receptor Biology, Advanced Medical Research Center, Nihon University School of Medicine, Ooyaguchi-kamimachi 30-1, Itabashi-ku, 173-8610, Tokyo, Japan. tnakayam@med.nihon-u.ac.jp
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakayama
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Buaijiaer
authors.initials: B
authors.lastname: Hasimu
authors.forename: Mikano
authors.initials: M
authors.lastname: Sato
authors.forename: Noriko
authors.initials: N
authors.lastname: Aoi
authors.forename: Kotoko
authors.initials: K
authors.lastname: Kosuge
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kanmatsuse
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kokubun
authors.forename: Jason D
authors.initials: JD
authors.lastname: Marrow
authors.forename: John A
authors.initials: JA
authors.lastname: Oates
mesh_terms: D000483:Alleles; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007438:Introns; D008297:Male; D008957:Models, Genetic; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D014176:Protein Biosynthesis; D012326:RNA Splicing
chemical_list: D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase