TY - JOUR
T1 - Molecular characterization of four novel mutations causing factor VII deficiency
AU - Tamary, Hannah
AU - Fromovich-Amit, Yonit
AU - Shalmon, Lea
AU - Zaizov, Rina
AU - Yaniv, Issac
AU - Klar, Aharon
AU - Peretz, Hava
AU - Brenner, Benjamin
AU - Lanir, Naomi
AU - Zivelin, Ariela
AU - Seligsohn, Uri
PY - 2000
Y1 - 2000
N2 - Introduction: 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. Patients and methods: Three patients with severe FVII deficiency (FVII activity ≤1%) and one with partial deficiency (25%) were studied. In all four patients, the FVII gene was amplified and sequenced. Results: 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. Conclusion: 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.
AB - Introduction: 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. Patients and methods: Three patients with severe FVII deficiency (FVII activity ≤1%) and one with partial deficiency (25%) were studied. In all four patients, the FVII gene was amplified and sequenced. Results: 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. Conclusion: 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.
KW - Factor VII
KW - Mutation
KW - Tissue factor
UR - http://www.scopus.com/inward/record.url?scp=0034584922&partnerID=8YFLogxK
U2 - 10.1038/sj.thj.6200062
DO - 10.1038/sj.thj.6200062
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AN - SCOPUS:0034584922
SN - 1466-4860
VL - 1
SP - 382
EP - 389
JO - Hematology Journal
JF - Hematology Journal
IS - 6
ER -