Identification of Three Novel Mutations in Hereditary Protein S Deficiency

Abstract

SummaryWe report the application of single-stranded conformation polymorphism (SSCP) analysis to the screening of 15 functionally important Protein S (PS) gene (PSα) regions (4.243 Kb) in 6 unrelated families with PS deficiencies. Direct sequencing of the fragments with altered migration patterns led to the identification of the corresponding molecular alterations. A missense mutation, G to T transversion at codon Cys598, and two different alterations, leading either to allelic exclusion, or premature termination of the protein translation: a G to A transition at codon Trp465 and a 1 nt (T) insertion at codon 265, were identified. The 1 nt insertion was observed in three apparently unrelated families but with a common geographical origin and the mutated allele was undetectable in platelet mRNAs of affected individuals. Family analysis confirmed, in each case, a perfect cosegregation of the mutation with the PS deficiency. We conclude that these alterations represent the causative mutations.

Co‐segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS1

“…Nevertheless, screening for PROS1 gene mutations has been performed in a number of studies. The proportion of cases where no mutations are detected varies widely between studies [10,17,[23][24][25][26][27][28][29][30][31][32][33]. When all cases are pooled together, PROS1 gene mutations are not detected in 47% of PS deficient families.…”

Optimization of a simple and rapid single-strand conformation analysis for detection of mutations in the PROS1 gene: Identification of seven novel mutations and three novel, apparently neutral, variants

“…Up to now many PROS1 mutations have been found associated with the PS-deficient phenotype [Gandrille et al, 1997]. Most of these mutations have been identified in the type I and in the few type II PS-deficient pedigrees, as well as in several pedigrees with coexistence of both type I and III phenotypes [Andersen et al, 1996;Beauchamp et al, 1996;Borgel et al, 1996;Bustorff et al, 1997;Simmonds et al, 1997;Espinosa-Parrilla et al, 1999]. By contrast, no PROS1 mutations clearly associated with the deficient phenotype are identified in most of the pedigrees presenting only the type III phenotype [Borgel, et al, 1996;Espinosa-Parrilla et al, 1997;Espinosa-Parrilla et al, 1999].…”

Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency

“…During the past few years, about 100 different mutations, most of them point mutations or short deletions or insertions, have been identified in the PROS1 gene of more than 135 PS-deficient proposita [Gandrille et al, 1997]. Most of the mutations have been reported to be associated with type I PS deficiency, some of which have been shown to cosegregate with both type I and III PS phenotypes coexisting in the same family [Anderson et al, 1996;Beauchamp et al, 1996;Bustorff et al, 1997;Li and Long, 1997;Mustafa et al, 1997a;Simmonds et al, 1997]. By contrast, although type III PS deficiency may be found at a similar or even higher prevalence than type I PS deficiency [Mateo et al, 1997], in a recent study no PROS1 mutation was found in more than 50% of the type III probands [Borgel et al, 1996].…”