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Moderation of hemophilia A phenotype by the factor V R506Q mutation
W C Nichols1, K Amano, P M Cacheris
1Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor 48109-0650, USA.
Blood
|August 15, 1996
Summary
The factor V R506Q mutation may reduce hemophilia A severity. This finding suggests that modifying the protein C pathway could be a new treatment strategy for factor VIII deficiency.
Area of Science:
- Genetics
- Hematology
- Molecular Biology
Background:
- Hemophilia A patients with identical factor VIII (FVIII) gene mutations can exhibit varying clinical severity.
- This phenotypic variability may stem from additional genetic factors modulating FVIII function.
Purpose of the Study:
- To investigate genetic modifiers of clinical severity in hemophilia A patients with common FVIII missense mutations.
- To explore the role of the factor V (FV) R506Q mutation in determining hemophilia A phenotype.
Main Methods:
- Molecular genetic analysis of potential modifying genes in unrelated hemophilia A patients.
- Exclusion of von Willebrand disease type 2N mutation (R91Q) as a modifier.
- Analysis of the factor V (FV) R506Q mutation (activated protein C resistance).
Main Results:
- Two common FVIII mutations (R1689C and R2209Q) were associated with both severe and mild/moderate hemophilia A.
- The FV R506Q mutation showed a correlation with reduced hemophilia A severity.
- Patients with reduced hemophilia A severity were heterozygous for FV R506Q, while severely affected patients were homozygous normal for FV.
Conclusions:
- Coinheritance of the FV R506Q mutation is a significant determinant of clinical phenotype in hemophilia A.
- Targeting the protein C pathway presents a potential novel therapeutic strategy for FVIII deficiency.