title: Point mutations regarded as missense mutations cause splicing defects in the factor XI gene.
abstract: BACKGROUND
  Point mutations within exons are frequently defined as missense mutations. In the factor (F)XI gene, three point mutations, c.616C>T in exon 7, c.1060G>A in exon 10 and c.1693G>A in exon 14 were reported as missense mutations P188S, G336R and E547K, respectively, according to their exonic positions. Surprisingly, expression of the three mutations in cells yielded substantially higher FXI antigen levels than was expected from the plasma of patients bearing these mutations.
  
  
  OBJECTIVE
  To test the possibility that the three mutations, albeit their positions within exons, cause splicing defects.
  
  
  RESULTS
  Platelet mRNA analysis of a heterozygous patient revealed that the c.1693A mutation caused aberrant splicing. Platelet mRNA of a second compound heterozygote for c.616T and c.1060A mutations was undetectable suggesting its degradation. Cells transfected with a c.616T minigene favored production of an aberrantly spliced mRNA that skips exon 7. Cells transfected with a mutated minigene spanning exons 8-10 exhibited a significant decrease in the amount of normally spliced mRNA. In silico analysis revealed that the three mutations are located within sequences of exonic splicing enhancers (ESEs) that bind special proteins and are potentially important for correct splicing. Compensatory mutations created near the natural mutations corrected the putative function of ESEs thereby restoring normal splicing of exons 7 and 10.
  
  
  CONCLUSIONS
  The present findings define a new mechanism of mutations in F11 and underscore the need to perform expression studies and mRNA analysis of point mutations before stating that they are missense mutations.
authors: The Amalia Biron Research Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel-Hashomer, Israel. michal.zucker@sheba.health.gov.il
authors: M
authors: M
authors: Zucker
authors: N
authors: N
authors: Rosenberg
authors: H
authors: H
authors: Peretz
authors: D
authors: D
authors: Green
authors: F
authors: F
authors: Bauduer
authors: A
authors: A
authors: Zivelin
authors: U
authors: U
authors: Seligsohn
mesh_terms: D000328:Adult; D005172:Factor XI / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D012326:RNA Splicing; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D005172:Factor XI