title: First molecular characterization of an unequal homologous alu-mediated recombination event responsible for hemophilia.
abstract: The large number of Alu repeats in the human genome provides abundant opportunities for unequal homologous recombination events that are responsible of several human diseases. We here describe a novel large FVIII gene deletion from a severe hemophilia A patient in which Alu-repetitive elements are directly involved in the origin of the mutation. Using a long-fragment PCR method, a approximately 23 kb deletion was delimited between introns 24 and 25. The resulting FVIII gene had a hybrid 2317-bp intron and lacked exon 25. Absence of exon 25 was confirmed at the RNA level. Multiple sequence alignment of this hybrid intron and normal introns 24 and 25 provided evidence of an homologous recombination event between two Alu repeats and the exact breakpoints were delimited to a 16 bp region. To our knowledge, this is the first report of hemophilia caused by unequal homologous Alu/Alu recombination. This mechanism, commonly related to genetic human disorders, may be involved in a significant number of hemophilia cases considering that FVIII is coded by an Alu-rich gene.
authors.affiliation: Unitat de Recerca del Centre de Transfusió i Banc de Teixits de Barcelona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Vidal
authors.forename: Elisenda
authors.initials: E
authors.lastname: Farssac
authors.forename: Joan
authors.initials: J
authors.lastname: Tusell
authors.forename: Lluís
authors.initials: L
authors.lastname: Puig
authors.forename: Dominique
authors.initials: D
authors.lastname: Gallardo
mesh_terms: D020087:Alu Elements / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002675:Child, Preschool; D005091:Exons; D005169:Factor VIII / Q000235:genetics; D006467:Hemophilia A / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008297:Male; D011995:Recombination, Genetic; D016415:Sequence Alignment; D017384:Sequence Deletion
chemical_list: D005169:Factor VIII