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A Mutation of the Active Protein S Gene Leading to an EGF1-Lacking
Protein in a Family With Qualitative (Type II) Deficiency
C. Leroy-Matheron,
M. Gouault-Heilmann,
M. Aiach, and
S. Gandrille
From INSERM U.428, Paris, France; and the Laboratoire
d'Hémostase, Hôpital Henri Mondor, Créteil, France.
The genomic analysis of a 70-year-old man with recurrent deep venous
thrombosis having a protein S (PS)-deficient phenotype corresponding to
both type III and type II evidenced two different mutations: a +5
g a mutation in the donor splice site of intron e (ivs e) and
a ser 460 to Pro mutation. The propositus' son, who had a type II PS
deficiency phenotype, only bore the ivs e +5 ga mutation.
The study of platelet PS mRNA prepared from this subject showed that
the ivs e, +5 ga mutation led to the generation of two
abnormal transcripts, one lacking exon 5 and the other lacking exons 5 and 6. The presence of an additional PS band with a decreased molecular
mass on immunoblots performed in reducing conditions suggested the
presence of truncated PS lacking EGF1 (encoded by exon 5). Two
monoclonal antibodies (MoAbs) were used to further characterize the
nonfunctional plasma PS. Comparison of PS levels measured with each of
these MoAbs and PS levels in conventional assays was consistent with
the presence of an abnormal inactive protein in the plasma of both
patients bearing the ivs e, +5 ga mutation, suggesting that
variant PS lacking EGF1 is secreted but is devoid of activated protein
C cofactor activity.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4608-4615
© 1998 by The American Society of Hematology.
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