Identification of the first alu-mediated large deletion involving the f5 gene in a compound heterozygous patient with severe factor v deficiency

Ilaria Guella, Elvezia Maria Paraboschi, Willem A. van Schalkwyk, Rosanna Asselta, Stefano Duga

Research output: Contribution to journalArticle

Abstract

Factor V (FV) deficiency is a rare autosomal recessive haemorrhagic disorder associated with moderate to severe bleeding symptoms. Conventional mutational screening leads to a complete molecular genetic diagnosis only in about 80-90% of cases. Large gene rearrangements, which could explain at least part of the "missing alleles" have not been reported so far in FV-deficient patients. In this work, we investigated a family with hereditary FV deficiency, in which the proband is compound heterozygous for a 205-Kb deletion, involving the first seven exons of F5, and the entire selectin P, L, and E genes, and for a novel splicing mutation (IVS12+5G>A). The deletion breakpoints, determined by using a combination of semi-quantitative real-time PCR and long PCR assays, occurred within AluY repeat sequences, suggesting an Alu-mediated unequal homologous recombination as the mechanism responsible for the deletion. The in vitro characterisation of the IVS12+5G>A mutation demonstrated that this mutation causes the skipping of exon 12 and the activation of a cryptic splice site. Low levels of residual wild-type splicing were also detectable, in agreement with the notion that the complete absence of FV may be not compatible with life.

Original languageEnglish
Pages (from-to)296-303
Number of pages8
JournalThrombosis and Haemostasis
Volume106
Issue number2
DOIs
Publication statusPublished - 2011

Keywords

  • Alu sequence
  • Coagulation factor V
  • Factor V deficiency
  • Large deletion
  • Splicing mutation

ASJC Scopus subject areas

  • Hematology

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