Molecular characterization of a factor VII deficient patient supports the importance of the second epidermal growth factor-like domain

• Published in: Haematologica (Roma) 2004-08, Vol.89 (8), p.979-984
• Main Authors: D'Andrea, G, Bossone, A, Lupone, MR, Peyvandi, F, Maisto, G, Perricone, F, Grandone, E, Margaglione, M
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; Cercopithecus aethiops; COS Cells; DNA Primers; Epidermal Growth Factor - genetics; Factor VII - genetics; Factor VII - metabolism; Factor VII Deficiency - blood; Factor VII Deficiency - genetics; Hematologic and hematopoietic diseases; Humans; Medical sciences; Mutation, Missense; Protein Folding; Transfection
• ISSN: 0390-6078; 1592-8721

Unita di Aterosclerosi e Trombosi, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy. BACKGROUND AND OBJECTIVES: Although a large number of gene mutations have been characterized in patients with factor VII (FVII) deficiency, few naturally occurring mutations have been described in epidermal growth factor (EGF)-like domains. We investigated a 6-year old Italian girl who had low functional and antigenic FVII plasma levels. DESIGN AND METHODS: Plasma levels of FVII activity and antigen were evaluated in the propositus and her relatives. Mutation screening was performed by sequencing the FVII gene. The effect of the identified FVII mutations was investigated by protein expression in transfected cells. RESULTS: The propositus was shown to be a compound heterozygote for a known (Arg110Cys) and a novel (Asp123Tyr) missense mutation both occurring in the second EGF-like domain. In transfected cells, expression of the Arg110Cys mutation reduced the amount of intracellular and secreted FVII protein (48% and 18%, respectively). Likewise, cells transfected with the Asp123Tyr mutation gave rise to low intracellular (40%) and extracellular (4%) FVII antigen levels. In conditioned media, FVII procoagulant activity was reduced accordingly (10% and