title: Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort.
abstract: Several cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however, these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17-18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships.
authors.affiliation: Haemostasis Research Group, Department of Cardiovascular Science, Faculty of Medicine, Dentistry and Health, University of Sheffield, Beech Hill Road, Sheffield, UK. d.hampshire@shef.ac.uk
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hampshire
authors.forename: Adel M
authors.initials: AM
authors.lastname: Abuzenadah
authors.forename: Ashley
authors.initials: A
authors.lastname: Cartwright
authors.forename: Nawal S
authors.initials: NS
authors.lastname: Al-Shammari
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Coyle
authors.forename: Michaela
authors.initials: M
authors.lastname: Eckert
authors.forename: Ahlam M
authors.initials: AM
authors.lastname: Al-Buhairan
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Messenger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Budde
authors.forename: Türkiz
authors.initials: T
authors.lastname: Gürsel
authors.forename: Jørgen
authors.initials: J
authors.lastname: Ingerslev
authors.forename: Ian R
authors.initials: IR
authors.lastname: Peake
authors.forename: Anne C
authors.initials: AC
authors.lastname: Goodeve
mesh_terms: D001483:Base Sequence; D018389:Codon, Nonsense; D015331:Cohort Studies; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics; D017384:Sequence Deletion; D014421:Turkey; D056725:von Willebrand Disease, Type 1 / Q000235:genetics; D056728:von Willebrand Disease, Type 2 / Q000235:genetics; D056729:von Willebrand Disease, Type 3 / Q000235:genetics; D014842:von Willebrand Diseases / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D050505:Mutant Proteins; D011994:Recombinant Proteins; D014841:von Willebrand Factor