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Molecular characterization of four novel mutations causing factor VII deficiency
H Tamary1, Y Fromovich-Amit, L Shalmon
1Pediatric Hematology-Oncology Center, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petah Tiqva 49 202, Israel. eytamary@netvision.net.il
Summary
This study identified four new mutations causing factor VII (FVII) deficiency, a rare bleeding disorder. Two mutations, when homozygous, led to severe bleeding, aiding in prenatal diagnosis of this coagulation defect.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Hereditary factor VII (FVII) deficiency is a rare coagulation disorder.
- Previous research identified the Ala244Val mutation in Israeli FVII-deficient patients.
- This study further investigates the molecular basis of FVII deficiency.
Observation:
- Four FVII-deficient patients (3 severe, 1 partial) were analyzed.
- The FVII gene was amplified and sequenced in all participants.
- Novel mutations were identified, including IVS 2+1G-->C, Phe 24 deletion, Leu300Pro, and Arg277His.
Findings:
- Homozygosity for IVS2+1G-->C was lethal; homozygosity for Phe 24 deletion led to severe bleeding.
- FVII modeling indicated Phe 24 is in the Gla domain.
- Arg 277 (catalytic domain, tissue factor binding) and Leu 300 (catalytic domain) mutations were found.
Implications:
- Two identified mutations (IVS2+1G-->C, Phe 24 deletion) are associated with severe bleeding in homozygous states, enabling prenatal diagnosis.
- Arg 277His may weaken tissue factor binding.
- Phe 24 deletion and Leu300Pro mutations might cause abnormal folding of Gla and catalytic domains, respectively.