Inherited factor VII deficiency: identification of two novel mutations (A191V and T239P) in the catalytic domain

Area of Science:

• Genetics
• Molecular Biology
• Hematology

Background:

• Coagulation Factor VII (FVII) deficiency can present with or without bleeding symptoms.
• Genetic mutations in F7 can lead to varying degrees of FVII deficiency.

Purpose of the Study:

• To identify and characterize novel mutations in the F7 gene.
• To investigate the molecular basis of FVII deficiency in patients without a bleeding history.

Main Methods:

• Genetic sequencing to identify F7 mutations.
• Phenotypic analysis including FVII activity (FVII:C) and antigen levels (FVII:Ag).
• Molecular modeling to understand the impact of mutations on FVII structure and function.

Main Results:

• Five missense F7 mutations (A191T, A191V, T239P, R224Q, M298I) were identified in four patients.
• Two novel homozygous mutations, A191V and T239P, were found in patients with no clinical bleeding.
• A191V mutation correlated with moderate type 1 FVII deficiency (FVII:C 4%, FVII:Ag 5%).
• T239P mutation correlated with mild type 2 FVII deficiency (FVII:C 25%, FVII:Ag 95%).
• Novel mutations are located near the FVII charge-stabilizing system.

Conclusions:

• Novel F7 mutations can result in FVII deficiency without causing bleeding.
• Molecular modeling provides insight into the loss-of-function mechanism of these mutations.
• Understanding genotype-phenotype correlations in FVII deficiency is crucial for clinical management.