Molecular characterization of four novel mutations causing factor VII deficiency

• Published in: The hematology journal : the official journal of the European Haematology Association Vol. 1; no. 6; p. 382
• Main Authors: Tamary, H, Fromovich-Amit, Y, Shalmon, L, Zaizov, R, Yaniv, I, Klar, A, Peretz, H, Brenner, B, Lanir, N, Zivelin, A, Seligsohn, U
• Format: Journal Article
• Language: English
• Published: England 2000
• Subjects: Adolescent; Adult; Amino Acid Substitution; Arabs - genetics; Catalytic Domain; Cerebral Hemorrhage - etiology; Chromosomes, Human, Pair 13 - genetics; Consanguinity; DNA Mutational Analysis; Factor VII - chemistry; Factor VII - genetics; Factor VII Deficiency - complications; Factor VII Deficiency - genetics; Fatal Outcome; Female; Humans; Hydrogen Bonding; Infant; Israel; Jews - genetics; Male; Models, Molecular; Mutation; Mutation, Missense; Pedigree; Point Mutation; Protein Structure, Secondary; Protein Structure, Tertiary; RNA Splice Sites - genetics; Sequence Deletion; Israel
• ISSN: 1466-4860
• DOI: 10.1038/sj.thj.6200062

Hereditary deficiency of factor VII (FVII) is a rare coagulation defect. We previously studied the molecular basis of the FVII deficiency in Israeli patients and found that the majority of them bore the Ala244Val mutation. In the present study we further analysed FVII deficient patients.
Three patients with severe FVII deficiency (FVII activity < or =1%) and one with partial deficiency (25%) were studied. In all four patients, the FVII gene was amplified and sequenced.
Four novel mutations have been identified: IVS 2+1G-->C Phe 24 deletion, Leu300Pro and Arg277His. Homozygosity for the IVS2+1G-->C mutation was lethal, whereas homozygosity for the Phe 24 deletion was accompanied by a severe bleeding tendency. FVII modeling showed that Phe 24 is located in the Gla domain. Both Arg 277 and Leu 300 are within the catalytic domain, although Arg 277 is also involved in tissue factor binding.
We have analysed four mutations, two of which (IVS2+1G-->C, Phe 24 deletion) were associated with severe bleeding tendency in the homozygous state, facilitating prenatal diagnosis. Hypothetically, using FVII modeling, Arg 277 replacement by histidine may weaken the tissue factor, while deletion of Phe 24 and Leu300Pro mutation might be associated with abnormal folding of the Gla and catalytic domains, respectively.