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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1443-1448
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT
20210G/A) affecting the prothrombinase complex in a
thrombophilic family
Elisabetta Castoldi,
Paolo Simioni,
Michael Kalafatis,
Barbara Lunghi,
Daniela Tormene,
Domenico Girelli,
Antonio Girolami, and
Francesco Bernardi
From the Department of Biochemistry and Molecular
Biology, Ferrara University, Ferrara, Italy; Department of
Medical and Surgical Sciences, University of Padua Medical School,
Padua, Italy; Department of Chemistry, Cleveland State
University, Cleveland OH; Department of Molecular Cardiology, Cleveland
Clinic Foundation, Cleveland OH; and Institute of Medical Pathology,
Chair of Internal Medicine, Verona University, Verona,
Italy.
The study of the molecular bases of thrombophilia in a large
family with 4 symptomatic members is reported. Three thrombophilic genetic components (FV R506Q, FV H1299R, and PT 20210G/A), all affecting the activity of the prothrombinase complex, were detected alone and in combination in various family members. In addition, a
newly identified missense mutation (factor V [FV] Y1702C), causing FV
deficiency, was also present in the family and appeared to enhance
activated protein C (APC) resistance in carriers of FV R506Q or FV
H1299R by abolishing the expression of the counterpart FV allele. The
relationships between complex genotypes, coagulation laboratory
findings, and clinical phenotypes were analyzed in the family. All
symptomatic family members were carriers of combined defects and showed
APC resistance and elevated F1 + 2 values. Evidence for the causative
role of the FV Y1702C mutation, which affects a residue absolutely
conserved in all 3 A domains of FV, factor VIII, and ceruloplasmin,
relies on (1) the absolute cosegregation between the
mutation and FV deficiency, both in the family and in the general
population; (2) FV antigen and immunoblot studies indicating the absence of Y1702C FV molecules in plasma of carriers of
the mutation, despite normal levels of the FV Y1702C messenger RNA; and
(3) molecular modeling data that support a crucial role of
the mutated residue in the A domain structure. These findings help to
interpret the variable penetrance of thrombosis in thrombophilic families and to define the molecular bases of FV deficiency.
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