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Moderation of hemophilia A phenotype by the factor V R506Q mutation
WC Nichols, K Amano, PM Cacheris, MS Figueiredo, K Michaelides, R Schwaab, L Hoyer, RJ Kaufman and D Ginsburg
Howard Hughes Medical Institute, University of Michigan Medical School, Ann
Arbor 48109-0650, USA.
Although many examples of unrelated hemophilia A patients carrying
identical point mutations in the factor VIII (FVIII) gene have been
reported, the clinical phenotype is not always the same among patients
sharing the same molecular defect. Possible explanations for this
discrepancy include undetected additional mutations in the FVIII gene or
coinheritance of mutations at other genetic loci that modulate FVIII
function. We report molecular genetic analysis of potential modifying genes
in two sets of unrelated patients carrying common FVIII missense mutations
but exhibiting different levels of clinical severity. Both mutations (FVIII
R1689C and R2209Q) are associated with severe hemophilia A in some patients
and mild/moderate disease in others. The common von Willebrand disease type
2N mutation (R91Q) was excluded as a modifying factor in these groups of
patients. However, analysis of the recently described factor V (FV) R506Q
mutation (leading to activated protein C resistance) identified a
correlation of inheritance of this defect with reduced hemophilia A
severity. Two moderately affected hemophilia A patients, each with either
of two FVIII gene mutations, were heterozygous for FV R506Q, whereas two
severely affected patients and two moderately affected patients were
homozygous normal at the FV locus. Our results suggest that coinheritance
of the FV R506Q mutation may be an important determinant of clinical
phenotype in hemophilia A and that modification of the protein C pathway
may offer a new strategy for the treatment of FVIII deficiency.
Volume 88,
Issue 4,
pp. 1183-1187,
08/15/1996
Copyright © 1996 by The American Society of Hematology
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