title: Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large kindred.
abstract: The incomplete penetrance of thrombosis in familial protein C deficiency suggests disease occurs when this deficit is combined with additional abnormalities in the hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred, which is affected by a clinically dominant type I protein C deficiency, provides strong evidence for a second unidentified gene that segregates independently of protein C deficiency and increases susceptibility to thrombosis. To test the second gene hypothesis, thirty-four candidate genes for proteins involved in hemostasis or inflammation were tested as the unknown defect, using highly polymorphic short tandem repeat (STR) markers in an informative subset (n = 31) of the kindred. The genes considered are; alpha-fibrinogen, beta-fibrinogen, gamma-fibrinogen, prothrombin, tissue factor, factor V, protein S, complement component 4 binding protein, factor XI, factor XII, factor XIIIa, factor XIIIb, histidine rich glycoprotein, high molecular weight kininogen, kallikrein, von Willebrands factor, platelet factor 4, thrombospondin, antithrombin III, alpha-1-antitrypsin, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, protein C inhibitor, alpha-2-plasmin inhibitor, kallistatin, lipoprotein a, interleukin 6, interleukin 1, cystathionine-beta-synthase, and methylenetetrahydrofolate reductase. Mutations in many of these genes have been previously established as independent risk factors for thrombosis. However, linkage analysis provided no evidence to implicate any of the candidate genes as the second inherited factor that promotes thrombophilia in this kindred.
authors.affiliation: Department of Pathology, University of Vermont, Burlington 05405, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Scott
authors.forename: E G
authors.initials: EG
authors.lastname: Bovill
authors.forename: P W
authors.initials: PW
authors.lastname: Callas
authors.forename: S J
authors.initials: SJ
authors.lastname: Hasstedt
authors.forename: M F
authors.initials: MF
authors.lastname: Leppert
authors.forename: J E
authors.initials: JE
authors.lastname: Valliere
authors.forename: T S
authors.initials: TS
authors.lastname: Varvil
authors.forename: G L
authors.initials: GL
authors.lastname: Long
mesh_terms: D001779:Blood Coagulation Factors / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D016678:Genome; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D020151:Protein C Deficiency / Q000150:complications / Q000235:genetics*; D020080:Tandem Repeat Sequences; D019851:Thrombophilia / Q000235:genetics*; D013927:Thrombosis / Q000209:etiology / Q000235:genetics
chemical_list: D001779:Blood Coagulation Factors; D001798:Blood Proteins; D005819:Genetic Markers