title: Two novel mutations in severe factor VII deficiency.
abstract: We have characterized the molecular defect in two families with severe factor VII (FVII) deficiency. In family I, the proband was found to be homozygous for a novel 18 bp deletion in exon 8 (g.10896-10913del) resulting in the in-frame deletion of six amino acids in the serine protease domain. Molecular modelling suggests the deletion is likely to disrupt folding of the FVII molecule. The reduced FVII antigen (21 U/dl) and negligible activity (0.4 U/dl) in the patient's plasma indicated that the deletion affected both the secretion/stability and function of the mutant protein. In family II, the proband was found to be a compound heterozygote for a novel missense mutation (g.7884G>A; FVII G117R) in exon 5 encoding the EGF2 domain of FVII and a nonsense mutation (g.8960C>T; FVII R152X) in exon 6. Extensive sequence comparison in a wide evolutionary context suggested that the Gly117 residue is critical for structure of FVII. The grossly reduced FVII antigen (1.1 U/dl) and activity (0.4 U/dl) plasma values indicate the mutation primarily affected the folding/secretion or stability of the protein.
authors.affiliation: Haemostasis and Thrombosis, MRC Clinical Sciences Centre, The Faculty of Medicine, Imperial College, Du Cane Road, London, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Gomez
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laffan
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Kemball-Cook
authors.forename: John
authors.initials: J
authors.lastname: Pasi
authors.forename: Mark
authors.initials: M
authors.lastname: Layton
authors.forename: Jack D
authors.initials: JD
authors.lastname: Singer
authors.forename: Edward G D
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: John H
authors.initials: JH
authors.lastname: McVey
mesh_terms: D000818:Animals; D001483:Base Sequence; D002675:Child, Preschool; D030541:Databases, Genetic; D005167:Factor VII / Q000235:genetics*; D005168:Factor VII Deficiency / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D005167:Factor VII