Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort

Daniel J. Hampshire; Adel M. Abuzenadah; Ashley Cartwright; Nawal S. Al-Shammari; Rachael E. Coyle; Michaela Eckert; Ahlam M. Al-Buhairan; Sarah L. Messenger; Ulrich Budde; Türkiz Gürsel; Jørgen Ingerslev; Ian R. Peake; Anne C. Goodeve

doi:10.1160/TH13-02-0135

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(02): 264-274
DOI: 10.1160/TH13-02-0135

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort

Daniel J. Hampshire

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Adel M. Abuzenadah

²Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

,

Ashley Cartwright

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Nawal S. Al-Shammari

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Rachael E. Coyle

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Michaela Eckert

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Ahlam M. Al-Buhairan

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Sarah L. Messenger

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Ulrich Budde

³Hemostaseology Department, Medilys Hamburg, Germany

,

Türkiz Gürsel

⁴Pediatric Hematology Unit, Gazi University School of Medicine, Ankara, Turkey

,

Jørgen Ingerslev

⁵Centre for Haemophilia and Thrombosis, University Hospital Skejby, Aarhus, Denmark

,

Ian R. Peake

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Anne C. Goodeve

¹Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

› Author Affiliations

Abstract

Summary

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.

Keywords

Large-scale deletion - multiplex ligation-dependent probe amplification - mutation analysis - recessive 2A - von Willebrand disease

Full Text

References

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