title: 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.
authors.affiliation: CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, 641 Avenue du Doyen Gaston Giraud, 34095 Montpellier Cedex 5, France. m-giansily@chu-montpellier.fr
authors.forename: Muriel
authors.initials: M
authors.lastname: Giansily-Blaizot
authors.forename: Estelle
authors.initials: E
authors.lastname: Lopez
authors.forename: Victoria
authors.initials: V
authors.lastname: Viart
authors.forename: Ouerdia
authors.initials: O
authors.lastname: Chafa
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tapon-Bretaudière
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Magali
authors.initials: M
authors.lastname: Taulan
mesh_terms: D000462:Algeria; D001777:Blood Coagulation; D051836:COUP Transcription Factors / Q000235:genetics; D002543:Cerebral Hemorrhage / Q000235:genetics*; D005167:Factor VII / Q000235:genetics*; D005168:Factor VII Deficiency / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter; D005817:Genetic Counseling; D005822:Genetic Vectors; D005838:Genotype; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D051836:COUP Transcription Factors; D051557:Hepatocyte Nuclear Factor 4; D005167:Factor VII