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Thromb Haemost 2001; 86(06): 1392-1399
DOI: 10.1055/s-0037-1616741
Review Article
Schattauer GmbH

Characterization and Structural Impact of Five Novel PROS1 Mutations in Eleven Protein S-deficient Families

Bente Damm Andersen
1   Departments of Clinical Biochemistry KB 3-01-1
,
Marie Luise Bisgaard
2   Clinical Genetics, Rigshospitalet,Copenhagen University Hospital, Copenhagen, Denmark
,
Bent Lind
1   Departments of Clinical Biochemistry KB 3-01-1
,
Malou Philips
1   Departments of Clinical Biochemistry KB 3-01-1
,
Bruno O. Villoutreix
3   INSERM U428, University of Paris V, School of Pharmacy, Paris, France
,
Sixtus Thorsen
1   Departments of Clinical Biochemistry KB 3-01-1
› Author Affiliations
Further Information

Publication History

Received 18 July 2001

Accepted after revision 12 September 2001

Publication Date:
12 December 2017 (online)

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Summary

Heterozygozity for four novel missense mutations (W108C, W342R, E349K and L485S) and one novel 4 bp deletion (ACdelAAAG affecting codons 632-633) was identified in PROS1 of unrelated thrombosis prone Danish families with protein S type I or III deficiency. The 4 bp deletion results in a frameshift leading to replacement of the coding sequence for the 3 C-terminal amino acids by an abnormal extended sequence that codes for 9 amino acids. The E349K substitution was found in 7 families. Haplotype analysis using 7 microsatellite markers flanking PROS1 was consistent with a common founder for this mutation. The mutations reported here are most likely the cause of the protein S deficiency. Firstly, the four missense mutations cosegre-gate with the abnormal plasma protein S phenotype and lead to the loss of highly conserved amino acids. Secondly, computer analysis of structural models of protein S predicts that the substitutions could affect proper protein folding and/or stability. Analysis of platelet mRNA from subjects with the W108C, E349K, L485S mutation or the 4 bp deletion showed that mutated mRNA was expressed in significant amounts suggesting that mutated molecules are synthesized. Our results are compatible with defective protein folding/unstable molecules, impaired secretion and intracellular degradation of mutated protein, which appear to be the major molecular disease mechanisms for missense mutations and certain other mutations found in genetic disorders.

Keywords

Protein S mutations - venous thromboembolism - founder effect - structural analysis
 

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