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Identification of 19 protein S gene mutations in patients with phenotypic
protein S deficiency and thrombosis. Protein S Study Group
RE Simmonds, H Ireland, G Kunz and DA Lane
Department of Haematology, Charing Cross and West-minster Medical School,
London, United Kingdom.
Protein S is a protein C-dependent and independent inhibitor of the
coagulation cascade. Deficiency of protein S is an established risk factor
for venous thromboembolism. We have used a strategy of specific
amplification of the coding regions and intron/exon boundaries of the
active protein S gene (PROS1) and direct single-strand solid phase
sequencing, to seek mutations in 35 individuals with phenotypic protein S
deficiency. Nineteen point mutations (16 novel) in 19 probands (or
relatives of probands) with venous thromboembolism are reported here.
Fifteen of the 19 mutations were expected to be causal and included 10
missense mutations (Lys9Glu, Glu26Ala, Gly54Glu, Cys145Tyr, Cys200Ser,
Ser283Pro, Gly340Asp, Cys408Ser, Ser460Pro, and Cys625Arg). Three of the 15
mutations resulted in premature stop codons (delete T 635 producing a stop
codon at position 126, Lys368stop and Tyr595stop) and two were at
intron/exon boundaries (+1 G to A in intron d and +3 A to C in intron j).
Of the remaining four mutations, three were within intronic sequence and
one was a silent mutation within the coding region and did not alter amino
acid composition. In two of the 10 missense mutations, reduced plasma
protein S activity compared with antigen level suggested the presence of
variant (type II) protein S.
Volume 88,
Issue 11,
pp. 4195-4204,
12/01/1996
Copyright © 1996 by The American Society of Hematology
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