S Elayaperumal1, N A Fouzia1, A Biswas2, S C Nair3, A Viswabandya4, B George1, A Abraham1, J Oldenburg2, E S Edison1, A Srivastava1. 1. Department of Hematology, Christian Medical College, Vellore, Tamil Nadu, India. 2. Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany. 3. Department of Immunohaematology & Transfusion Medicine, Christian Medical College, Vellore, Tamil Nadu, India. 4. Princess Margaret Cancer Center, Toronto, Ontario, Canada.
Abstract
INTRODUCTION: Type 3 von Willebrand disease (VWD) is the rare and most severe form of VWD which results from a near-complete deficiency of the von Willebrand factor (VWF). This study evaluates in detail the molecular pathology of type-3 VWD in India. One hundred and two patients from 90 families were evaluated. PATIENTS AND METHODS: Phenotypic data, including bleeding scores (BS), were documented using structured questionnaires. Diagnosis of type 3 VWD was based on undetectable VWF antigen levels in the plasma. Genomic DNA from these patients was screened for mutations in VWF gene. Structural modeling and expression studies were carried out for missense mutations. RESULTS: Out of 102 patients, mutations could be identified in 91% (n = 93). Fifty-five different gene variants were identified. Thirty-four (61.8%) were novel. Mutations could be identified in both the alleles in 90 patients, while no causative mutation could be identified in 9 patients; twenty-four (23.5%) patients had mutations clustered in the propeptide region of VWF. Interestingly, five mutations accounted for the defects in 37/93 (39.8%) patients. Structural analysis and in vitro studies on missense mutations imply impaired processes associated with secretion of VWF. CONCLUSION: This study is one of the largest series to define the molecular basis of type-3 VWD.
INTRODUCTION: Type 3 von Willebrand disease (VWD) is the rare and most severe form of VWD which results from a near-complete deficiency of the von Willebrand factor (VWF). This study evaluates in detail the molecular pathology of type-3 VWD in India. One hundred and two patients from 90 families were evaluated. PATIENTS AND METHODS: Phenotypic data, including bleeding scores (BS), were documented using structured questionnaires. Diagnosis of type 3 VWD was based on undetectable VWF antigen levels in the plasma. Genomic DNA from these patients was screened for mutations in VWF gene. Structural modeling and expression studies were carried out for missense mutations. RESULTS: Out of 102 patients, mutations could be identified in 91% (n = 93). Fifty-five different gene variants were identified. Thirty-four (61.8%) were novel. Mutations could be identified in both the alleles in 90 patients, while no causative mutation could be identified in 9 patients; twenty-four (23.5%) patients had mutations clustered in the propeptide region of VWF. Interestingly, five mutations accounted for the defects in 37/93 (39.8%) patients. Structural analysis and in vitro studies on missense mutations imply impaired processes associated with secretion of VWF. CONCLUSION: This study is one of the largest series to define the molecular basis of type-3 VWD.
Authors: Erik Berntorp; Sonata S Trakymienė; Augusto B Federici; Katharina Holstein; Fernando F Corrales-Medina; Glenn F Pierce; Alok Srivastava; Mario von Depka Prondzinski; Jill M Johnsen; Irena P Zupan; Susan Halimeh; Vuokko Nummi; Jonathan C Roberts Journal: Haemophilia Date: 2022-07 Impact factor: 4.263
Authors: Luciano Baronciani; Ian Peake; Reinhard Schneppenheim; Anne Goodeve; Minoo Ahmadinejad; Zahra Badiee; Mohammad-Reza Baghaipour; Olga Benitez; Imre Bodó; Ulrich Budde; Andrea Cairo; Giancarlo Castaman; Peyman Eshghi; Jenny Goudemand; Wolf Hassenpflug; Hamid Hoorfar; Mehran Karimi; Bijan Keikhaei; Riitta Lassila; Frank W G Leebeek; Maria Fernanda Lopez Fernandez; Pier Mannuccio Mannucci; Renato Marino; Nikolas Nikšić; Florian Oyen; Cristina Santoro; Andreas Tiede; Gholamreza Toogeh; Alberto Tosetto; Marc Trossaert; Eva M K Zetterberg; Jeroen Eikenboom; Augusto B Federici; Flora Peyvandi Journal: Blood Adv Date: 2021-08-10