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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
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Adel M. Abuzenadah
2   Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
,
Ashley Cartwright
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Nawal S. Al-Shammari
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Rachael E. Coyle
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Michaela Eckert
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Ahlam M. Al-Buhairan
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Sarah L. Messenger
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Ulrich Budde
3   Hemostaseology Department, Medilys Hamburg, Germany
,
Türkiz Gürsel
4   Pediatric Hematology Unit, Gazi University School of Medicine, Ankara, Turkey
,
Jørgen Ingerslev
5   Centre for Haemophilia and Thrombosis, University Hospital Skejby, Aarhus, Denmark
,
Ian R. Peake
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Anne C. Goodeve
1   Haemostasis Research Group, Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
› Author Affiliations Financial support: This study was supported by the National Institutes of Health program project grant HL081588 Zimmerman Program for the Molecular and Clinical Biology of VWD (DJH, IRP and ACG), King Abdulaziz University in Saudi Arabia (AM Abuzenadah), the UK Medical Research Council (AC) and King Saud University in Saudi Arabia (AM AlBuhairan).
Further Information

Publication History

Received: 17 February 2013

Accepted after minor revision: 04 May 2013

Publication Date:
04 December 2017 (online)

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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

 

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