title: A novel mutation in intron K of the PROS1 gene causes aberrant RNA splicing and is a common cause of protein S deficiency in a UK thrombophilia cohort.
abstract: In the course of investigating the molecular basis of protein S deficiency in 31 index cases with thrombophilia, we identified seven kindred where the underlying defect was a novel A to G transition 9 bp upstream of exon 12 in intron K of the PROS1 gene. In all but one case, the mutation caused type I deficiency. One individual had type III deficiency. While ectopic transcript analysis using the BstXI dimorphism in exon 15 failed to detect a transcript from the mutated allele, analysis of transcripts spanning exons 11 and 12 revealed a minor mRNA species. Sequencing confirmed the mutation created a new RNA acceptor site introducing 8 nucleotides of intronic sequence into the mature mRNA. Haplotype analysis of the defective PROS1 alleles in six families revealed the same haplotype in all affected individuals suggesting the presence of a common ancestor. Six of the fourteen relatives with the mutation experienced at least one venous thrombotic event strongly supporting the association of the mutation with venous thrombosis.
authors.affiliation: Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, Sheffield, UK. n.j.beauchamp@sheffield.ac.uk
authors.forename: N J
authors.initials: NJ
authors.lastname: Beauchamp
authors.forename: M E
authors.initials: ME
authors.lastname: Daly
authors.forename: M
authors.initials: M
authors.lastname: Makris
authors.forename: F E
authors.initials: FE
authors.lastname: Preston
authors.forename: I R
authors.initials: IR
authors.lastname: Peake
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005165:Factor V / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017293:Protein S / Q000235:genetics*; D018455:Protein S Deficiency / Q000453:epidemiology / Q000235:genetics*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D019851:Thrombophilia / Q000453:epidemiology / Q000235:genetics*; D013924:Thrombophlebitis / Q000453:epidemiology / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D017293:Protein S; D012333:RNA, Messenger; C095381:factor V Leiden; D005165:Factor V