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Factor VNew Brunswick: Ala221-to-Val substitution results in reduced
cofactor activity
JM Murray, MD Rand, JO Egan, S Murphy, HC Kim and KG Mann
Department of Biochemistry, University of Vermont College of Medicine,
Burlington 05405-0068, USA.
We have characterized the factor V protein and cDNA of a patient displaying
factor V deficiency (parahemophilia) and correlated the reduced activity
with a missense mutation of Ala221-to-Val. Plasma from the subject
individual (C1) presented reduced factor V antigen (39% of normal) that
displayed reduced activity (approximately 26% of normal). Factor V purified
from this individual by standard techniques shows normal migration on
sodium dodecyl sulfate gels and a normal pattern of activation by thrombin.
Purified antigen from sibling C2 gives a much reduced specific activity of
263 U/mg (17% of normal). Sibling C3, the mother, and the father have
antigen within the normal range (57% to 200%) that has approximately normal
specific activity. The cDNA encoding the factor Va heavy and light chains
of the subject individual was polymerase chain reaction-amplified and
sequenced and revealed an A- to-G substitution at position 3 of codon 51
(silent mutation), a C-to-T substitution in position 2 of codon 221
(Ala221-Val), a T-to-C substitution at position 3 of codon 708 (silent
mutation), and a G-to-A substitution at position 1 of codon 2185
(Thr2185-Ala). The latter mutation was also observed in control individuals
and is proposed to be a possible polymorphism. Restriction analyses
demonstrated the presence of one mutant and one normal allele in the
father. The subject individual (C1) and sibling C2 carry only the mutant
allele. The mother and sibling C3 carry only the normal allele. The
inheritance pattern suggests the presence of a missing or nonexpressed
allele in the mother that is passed on to all the siblings. Expression of
only the mutant allele by the subject individual (C1) and sibling C2 is
consistent with reduced factor V antigen and activity in these patients. We
have designated this mutant as Factor VNew Brunswick.
Volume 86,
Issue 5,
pp. 1820-1827,
09/01/1995
Copyright © 1995 by The American Society of Hematology
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