Original ArticlesCharacterization of the human prostaglandin H synthase 1 gene (PTGS1): exclusion by genetic linkage analysis as a second modifier gene in familial thrombosisScott, B. T.; Hasstedt, S. J.; Bovill, E. G.; Callas, P. W.; Valliere, J. E.; Wang, L.; Wu, K. K.; Long, G. L.Author Information B. T. Scott, E. G. Bovill and J. E. Valliere are with the Department of Pathology, P. W. Callas is with the Biometry Facility, and G.L. Long is with the Department of Biochemistry, University of Vermont, Burlington, Vermont, USA; S. J. Hasstedt is with the Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA; and L. Wang and K. K. Wu are with the Division of Hematology, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA. (Received 31 October 2001; revised 22 March 2002; accepted 2 April 2002) Sponsorship: This work was supported in part by USPHS grant HL 46703. Address correspondence to B. T. Scott, Department of Pathology, University of Vermont, Burlington, VT 05405, USA. Tel: (+1) 802 656 4333; fax: (+1) 802 862 8229; e-mail: email@example.com Blood Coagulation & Fibrinolysis: September 2002 - Volume 13 - Issue 6 - p 519-531 Buy Abstract Genetic evidence from a large Vermont kindred indicates that an unknown gene promotes thrombosis when inherited in conjunction with type I protein C deficiency. Cyclooxygenase-1 [prostaglandin H synthase 1 gene (PTGS1)] was tested as a plausible candidate for the unknown gene because of its role in primary hemostasis. The complete sequence of PTGS1 (25 638 nucleotides) was determined from a 37 kb human genomic cosmid clone to characterize intronic regions and subsequently to allow the search for mutations by direct sequencing of genomic DNA. Northern blot analysis confirms usage of a newly described distal poly-adenylation signal. Short tandem repeat (STR) sequences found in intron 2 and the 3′ flanking region were developed as new genetic markers for PTGS1. The position of PTGS1 was refined on the CHLC chromosome 9 linkage map using the new markers scored in four Centre d'Etude du Polymorphisme Humain families and multipoint linkage analysis. Direct sequencing of DNA from members of the Vermont kindred led to the discovery of two new single nucleotide polymorphisms (SNPs) that give rise to non-conservative amino acid changes in the signal peptide (Arg8 to Trp and Pro17 to Leu) of cyclooxygenase-1. Linkage analysis of the SNP and STR markers indicated that PTGS1 is not the interacting gene associated with an increased incidence of thrombosis in the Vermont kindred. © 2002 Lippincott Williams & Wilkins, Inc.