Summary
Protein S deficiency is a dominantly inherited disorder that results from mutations
in the PROS1 gene. Previous sequencing of the gene failed to detect mutations in eight out of
18 investigated Swedish families, whereas segregation analyses detected large deletions
in three out of the eight families. The present study investigates more thoroughly
for the presence of deletions but also for other types of rearrangements. FISH analysis
confirmed the existence of the three previously identified large deletions, but failed
to identify any other type of rearrangement among the eight analysed families. MLPA
analysis of the PROS1 gene revealed two smaller deletions covering two and four exons, respectively. Thus,
deletions could be found in five out of eight families where no point mutations could
be found despite sequencing of the gene. Twelve additional, not previously analysed,
families were subsequently analysed using MLPA. The analysis identified two smaller
deletions (3 and 4 exons). Including all PS-deficient families, i.e. also the 10 families
where sequencing found a causative point mutation, deletions were identified in seven
out of 30 PS-deficient families. A strategy of sequencing followed by MLPA analysis
in mutation-negative families identified the causative mutation in 15 out of 18 of
Swedish PS-deficient families. Most deletions were different as determined by their
sizes, locations and flanking haplotypes. FISH (8 families) and MLPA analysis (20
families) failed to identify other types of rearrangements.
Keywords
Protein C/S pathway - molecular biology methods - familial thrombosis - venous thrombosis
- thrombophilia
