Compound heterozygosity involving Antithrombin Cambridge II (p.Ala416Ser) in antithrombin deficiency

Águila, Sonia; Martínez‐Martínez, Irene; Collado, M. A. Garrido; Llamas, Pilar; Antón, Ana Isabel; Martínez-Redondo, Consuelo; Padilla, José; Iniesta, Juan Antonio; Morena‐Barrio, María Eugenia de la; García-Avello, Ángel; Vicente, Vicente; Corral, Javier

doi:10.1160/th12-09-0707

Cited by 2 publications

(1 citation statement)

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“…Two of these defects are restricted to the index family, but one, the c.42-1060_-1057dupTTGA affecting one VDRE of intron 1, is a new low prevalent polymorphism in Spain (MAF: 0.013) with moderate functional consequences. The functional consequences of the c.42-1060_-1057dupTTGA polymorphism might also modulate the risk of venous thrombosis in patients with other genetic defect causing antithrombin deficiency, as it has recently described for antithrombin Cambridge variants, a relatively frequent variation of SERPINC1 [ 31 ].Finally, the potential role in thrombosis of this new polymorphism should be evaluated in large case/control studies.…”

Section: Discussionmentioning

confidence: 99%

Identification of Regulatory Mutations in SERPINC1 Affecting Vitamin D Response Elements Associated with Antithrombin Deficiency

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%