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
