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Lethal factor VII deficiency due to novel mutations in the F7 promoter: Functional analysis reveals disruption of HNF4 binding site

Abstract : Hereditary factor VII (FVII) deficiency is a rare autosomal recessive disorder. Deleterious mutations that prevent the synthesis of any amount of functional FVII have been associated with life-threatening haemorrhage in neonates. Here we report two infants, of Maghrebian origin, who suffered a fatal spontaneous cerebral haemorrhage. Investigation of the molecular basis for their severe FVII deficiency revealed novel mutations in a homozygous state within the F7 gene promoter: a single nucleotide substitution (c.-65G>C) and a 2bp deletion (c.-60_-59delTT). To determine whether these promoter variants were responsible for the FVII deficiency, computer-assisted sequence analyses were performed. The data predicted a disrupted binding of both HNF4 and COUP-TF transcription factors with each variant. Concordantly, experimental results revealed an altered HNF4-induced transactivation in the promoter mutated variants. The execution of functional tests is critical to ensuring a complete understanding of the effect of any promoter mutant on FVII deficiency. Only then can an accurate molecular diagnosis be made and further genetic counselling and prenatal diagnosis be offered.
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https://hal.umontpellier.fr/hal-02443306
Contributeur : Karine Deletang <>
Soumis le : vendredi 17 janvier 2020 - 09:29:01
Dernière modification le : mercredi 25 mars 2020 - 17:18:44

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Muriel Giansily-Blaizot, Estelle Lopez, Victoria Viart, Ouerdia Chafa, Jacqueline Tapon-Bretaudière, et al.. Lethal factor VII deficiency due to novel mutations in the F7 promoter: Functional analysis reveals disruption of HNF4 binding site. Thrombosis and Haemostasis, Schattauer, 2017, 108 (08), pp.277-283. ⟨10.1160/TH11-09-0638⟩. ⟨hal-02443306⟩

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