title: Regulatory regions of SERPINC1 gene: identification of the first mutation associated with antithrombin deficiency.
abstract: Antithrombin is the main endogenous anticoagulant. Impaired function or deficiency of this molecule significantly increases the risk of thrombosis. We studied the genetic variability of  SERPINC1 , the gene encoding antithrombin, to identify mutations affecting regulatory regions with functional effect on its levels. We sequenced 15,375 bp of this gene, including the potential promoter region, in three groups of subjects: five healthy subjects with antithrombin levels in the lowest (75%) and highest (115%) ranges of our population, 14 patients with venous thrombosis and a moderate antithrombin deficiency as the single thrombophilic defect, and two families with type I antithrombin deficiency who had neither mutations affecting exons or flanking regions, nor gross gene deletions. Our study confirmed the low genetic variability of  SERPINC1 , particularly in the coding region, and its minor influence in the heterogeneity of antithrombin levels. Interestingly, in one family, we identified a g.2143 C>G transversion, located 170 bp upstream from the translation initiation codon. This mutation affected one of the four regions located in the minimal promoter that have potential regulatory activity according to previous DNase footprinting protection assays. Genotype-phenotype analysis in the affected family and reporter analysis in different hepatic cell lines demonstrated that this mutation significantly impaired, although it did not abolish, the downstream transcription. Therefore, this is the first mutation affecting a regulatory region of the  SERPINC1  gene associated with antithrombin deficiency. Our results strongly sustain the inclusion of the promoter region of  SERPINC1  in the molecular analysis of patients with antithrombin deficiency.
authors.affiliation: Centro Regional de Hemodonación, University of Murcia, Spain.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: de la Morena-Barrio
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Antón
authors.forename: Irene
authors.initials: I
authors.lastname: Martínez-Martínez
authors.forename: José
authors.initials: J
authors.lastname: Padilla
authors.forename: Antonia
authors.initials: A
authors.lastname: Miñano
authors.forename: José
authors.initials: J
authors.lastname: Navarro-Fernández
authors.forename: Sonia
authors.initials: S
authors.lastname: Águila
authors.forename: María Fernanda
authors.initials: MF
authors.lastname: López
authors.forename: Jordi
authors.initials: J
authors.lastname: Fontcuberta
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
mesh_terms: D000328:Adult; D000990:Antithrombin III / Q000235:genetics*; D020152:Antithrombin III Deficiency / Q000150:complications / Q000235:genetics*; D001777:Blood Coagulation / Q000235:genetics; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D013030:Spain; D015533:Transcriptional Activation / Q000235:genetics; D020246:Venous Thrombosis / Q000209:etiology / Q000235:genetics*
chemical_list: C542513:SERPINC1 protein, human; D000990:Antithrombin III