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Thromb Haemost 2012; 108(02): 277-283
DOI: 10.1160/TH11-09-0638
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

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

Muriel Giansily-Blaizot   *
1   CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France
2   INSERM U827, Laboratoire de Génétique de Maladies Rares, Montpellier, France
3   Université Montpellier1, UFR de Médecine, Montpellier, France
,
Estelle Lopez   *
2   INSERM U827, Laboratoire de Génétique de Maladies Rares, Montpellier, France
3   Université Montpellier1, UFR de Médecine, Montpellier, France
,
Victoria Viart   *
2   INSERM U827, Laboratoire de Génétique de Maladies Rares, Montpellier, France
3   Université Montpellier1, UFR de Médecine, Montpellier, France
,
Ouerdia Chafa
4   Centre de transfusion, Hôpital Mustapha, Algiers, Algeria
,
Jacqueline Tapon-Bretaudière
5   Laboratoire d’Hématologie, Hôpital Européen Georges Pompidou, APHP, Paris, France
6   INSERM U765, Université Paris-Descartes, Paris, France
,
Mireille Claustres
1   CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France
2   INSERM U827, Laboratoire de Génétique de Maladies Rares, Montpellier, France
3   Université Montpellier1, UFR de Médecine, Montpellier, France
,
Magali Taulan
2   INSERM U827, Laboratoire de Génétique de Maladies Rares, Montpellier, France
3   Université Montpellier1, UFR de Médecine, Montpellier, France
› Author Affiliations Financial support: This work was supported in part by the Centre Hospitalier Universitaire of Montpellier and in part by a grant from NovoNordisk (n°010853/HAEM/4/3). The collaboration with Dr O Chafa in Algiers was supported by a grant from INSERM-DPGRF.
Further Information

Publication History

Received: 15 September 2011

Accepted after major revision: 02 May 2012

Publication Date:
25 November 2017 (online)

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Summary

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.

Keywords

FVII deficiency - promoter mutation - HNF4 - COUP-TF1

* These authors contributed equally.


 

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