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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 173-179
Protein S secretion differences of missense mutants account
for phenotypic heterogeneity
Yolanda Espinosa-Parrilla,
Tomio Yamazaki,
Nùria Sala,
Björn Dahlbäck, and
Pablo García de Frutos
From the Department of Clinical Chemistry, Lund University,
University Hospital, Malmö, Sweden; and Centre de Genètica
Mèdica i Molecular, Institut de Recerca Oncològica (IRO),
Barcelona, Spain.
To elucidate the molecular background for the heterogeneity in
protein S plasma concentrations observed in protein S deficient individuals, the in vitro synthesis of recombinant protein S missense mutants was investigated. Six different naturally occurring mutations identified in the protein S gene (PROS1) of thrombosis patients were reproduced in protein S cDNA by site directed mutagenesis. Two
mutants, G441C and Y444C (group A), were associated with low total
plasma concentration of protein S. Modestly low protein S was found in
families with R520G and P626L (group B) mutants. T57S and I518M (group
C), which was associated with marginally low protein S, did not
segregate with protein S deficiency in the respective families, raising
doubts as to whether they were causative mutations or rare neutral
variants. The 6 protein S mutants were transiently expressed in COS 1 cells. The Y444C mutant showed the lowest level of secretion (2.5%)
followed by the G441C mutant (40%). Group B demonstrated around 50%
reduction in secretion, whereas group C mutants showed normal
secretion. Pulse-chase experiments demonstrated impaired protein S
processing with intracellular degradation and decreased secretion into
the culture media of group A and B mutants. Interestingly, there was a
good correlation between in vitro secretion and the concentration of
free protein S in the plasma of heterozygous carriers. These results
demonstrate impaired protein S secretion to be an important mechanism
underlying hereditary protein S deficiency and that variations in
protein secretion is a major determinant of the phenotypic
heterogeneity observed in protein S deficiency. (Blood.
2000;95:173-179)
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