title: Combined partial exon skipping and cryptic splice site activation as a new molecular mechanism for recessive type 1 von Willebrand disease.
abstract: We describe the complex picture associated with a mutated splice junction in intron 13 of von Willebrand factor (VWF) gene. The proband, characterized by a marked decrease in plasma and platelet VWF and near normal multimer organization, was classified as recessive type 1 von Willebrand disease (VWD). Genetic analysis demonstrated that he was homozygous for the 1534-3C > A mutation in the consensus sequence of the acceptor splicing site of intron 13 of the VWF gene. Platelet mRNA analysis documented three VWF transcripts: a wild type generated by the correct recognition of the mutated splice site, a smaller transcript not containing exon 14, and a longer one that, in addition to exons 13 and 14, included a 62bp fragment corresponding to the end of intron 13. The small transcript derives from the skipping of exon 14, the long one from the activation of a cryptic splice site in intron 13; both show a premature stop codon in VWF propeptide, so the proband VWF derives entirely from the correct splice site recognition. Combined incomplete exon skipping and cryptic splice site activation are first recognized in VWD. Since the 1534-3C > A mutation does not abolish the normal processing of mRNA, it is unlikely to be found in type 3 VWD. This mutation therefore appears to be peculiar to type 1 VWD.
authors.affiliation: Department of Medical and Surgical Sciences, University of Padua Medical School, secondchairof internal Medicine, Padua, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Gallinaro
authors.forename: Francesca
authors.initials: F
authors.lastname: Sartorello
authors.forename: Elena
authors.initials: E
authors.lastname: Pontara
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cattini
authors.forename: Antonella
authors.initials: A
authors.lastname: Bertomoro
authors.forename: Lucia
authors.initials: L
authors.lastname: Bartoloni
authors.forename: Antonio
authors.initials: A
authors.lastname: Pagnan
authors.forename: Alessandra
authors.initials: A
authors.lastname: Casonato
mesh_terms: D000225:Adenine; D000328:Adult; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000378:metabolism; D003596:Cytosine; D004252:DNA Mutational Analysis; D005091:Exons; D005169:Factor VIII / Q000378:metabolism; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D010375:Pedigree; D010979:Platelet Function Tests; D022821:RNA Splice Sites; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D022821:RNA Splice Sites; D012333:RNA, Messenger; D014841:von Willebrand Factor; D003596:Cytosine; D005169:Factor VIII; D000225:Adenine