title: Identification of Regulatory Mutations in SERPINC1 Affecting Vitamin D Response Elements Associated with Antithrombin Deficiency.
abstract: Antithrombin is a crucial anticoagulant serpin whose even moderate deficiency significantly increases the risk of thrombosis. Most cases with antithrombin deficiency carried genetic defects affecting exons or flanking regions of SERPINC1.We aimed to identify regulatory mutations inSERPINC1 through sequencing the promoter, intron 1 and 2 of this gene in 23 patients with antithrombin deficiency but without known genetic defects. Three cases with moderate antithrombin deficiency (63-78%) carried potential regulatory mutations. One located 200 bp before the initiation ATG and two in intron 1. These mutations disrupted two out of five potential vitamin D receptor elements (VDRE) identified in SERPINC1 with different software. One genetic defect, c.42-1060_-1057dupTTGA, was a new low prevalent polymorphism (MAF: 0.01) with functional consequences on plasma antithrombin levels. The relevance of the vitamin D pathway on the regulation of SERPINC1 was confirmed in a cell model. Incubation of HepG2 with paricalcitol, a vitamin D analog, increased dose-dependently the levels of SERPINC1transcripts and antithrombin released to the conditioned medium. This study shows further evidence of the transcriptional regulation of SERPINC1 by vitamin D and first describes the functional and pathological relevance of mutations affecting VDRE of this gene. Our study opens new perspectives in the search of new genetic defects involved in antithrombin deficiency and the risk of thrombosis as well as in the design of new antithrombotic treatments.
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Mara
authors.initials: M
authors.lastname: Toderici
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: de la Morena-Barrio
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Padilla
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Miñano
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Antón
authors.affiliation: Servicio de Neurología, Hospital Universitario Reina Sofía, Murcia, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Iniesta
authors.affiliation: Servicio de Medicina Interna, Hospital Universitario Morales Meseguer, Murcia, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Herranz
authors.affiliation: Servicio de Hematología y Hemoterapia, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Fernández
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.affiliation: Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000990:Antithrombin III / Q000235:genetics*; D020152:Antithrombin III Deficiency / Q000235:genetics*; D045744:Cell Line, Tumor; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D013923:Thromboembolism / Q000235:genetics; D013927:Thrombosis / Q000235:genetics; D030181:Vitamin D Response Element / Q000235:genetics*
chemical_list: C542513:SERPINC1 protein, human; D000990:Antithrombin III