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.