The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population

SummaryThe molecular basis of protein S (PS) deficiency was investigated in seven ofeight donors identified with persistently low plasma PS levels from a survey ofPS levels in 3788 Scottish blood donors. PROS1 gene analysis identified atleast one defect in six donors. Five were heterozygous for the Heerlenpolymorphism predicting a Ser460Pro substitution. Haplotype analysisrevealed the possibility that this allele was inherited with the samehaplotype in four of the five donors, suggesting a founder effect for theHeerlen allele in this population. One Heerlen allele carrier was alsoheterozygous for a 3 bp deletion 68–72 bp upstream of exon 2. PlateletPROS1 transcript analysis showed no reduction in mRNA expression fromthe affected allele in this donor. A T to G transversion 3 bp upstream of exon12 was identified in one donor, which is predicted to reduce the efficiency ofPS mRNA splicing. However, PROS1 transcript analysis showed no evidenceof exon skipping or cryptic splicing. No PROS1 gene defect was detected inthe remaining donor. This genetic information enabled us to refine ourestimate of the prevalence of heritable PS deficiency in the Scottishpopulation to between 0AE16% and 0AE21%, predominantly resulting from thepresence of the Heerlen allele.Keywords: protein S deficiency, Heerlen allele, splice site defect.