HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Brief report Factor VII gene intronic mutation in a lethal factor VII deficiency: effects on splice-site selection

نویسندگان

  • Keren Borensztajn
  • Marie-Laure Sobrier
  • Anne-Marie Fischer
  • Ouerdia Chafa
  • Serge Amselem
  • Jacqueline Tapon-Bretaudière
چکیده

In a patient with lethal factor VII (FVII) deficiency, 2 homozygous nucleotide substitutions were identified in the F7 gene: a IVS7 2T>G transversion involving the IVS7 donor splice site, followed by a mutation at nucleotide 10588 that would result in a missense variation (Arg224Gln). The mutated splice site, located within the first repeat of a minisatellite, is followed by a variable number of pseudo-sites, normally silent. To investigate the consequences of this mutation on F7 splicing, we designed normal and mutant minigenes, spanning exons 5 to 8. In cells transfected with the mutant construct, no normal splicing occurred. Only spliced transcripts including the first minisatellite repeat were observed, resulting from the activation of the most proximal wild-type pseudo-site, which would generate a truncatedprotein (stopcodonupstreamofnucleotide 10588). These findings, which suggest the existence of a mechanism selecting one single splice site among multiple cryptic sites, explain the patient’s phenotype. (Blood. 2003;102:561-563)

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تاریخ انتشار 2003