Novel point mutation in a leucine-rich repeat of the GPIb{alpha} chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard-Soulier syndrome affecting two unrelated families: the N41H variant

• Published in: Haematologica (Roma) 2008-09, Vol.93 (11), p.1743-1747
• Main Authors: Vettore, Silvia, Scandellari, Raffaella, Moro, Stefano, Lombardi, Anna Maria, Scapin, Margherita, Randi, Maria Luigia, Fabris, Fabrizio
• Format: Article
• Language: English
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.12830

1 Department of Medical and Surgical Sciences and 2 Molecular Modeling Section, Department of Pharmaceutical Sciences, University of Padova Medical School, Padova, Italy Correspondence: Fabrizio Fabris, Chair of Internal Medicine, Department of Medical and Surgical Sciences, via Giustiniani 1, 35128 Padova, Italy., E-mail: fabrizio.fabris{at}unipd.it ABSTRACT In Italy, a significant proportion of patients with autosomal dominant inheritance of macrothrombocytopenia have been recognized as having heterozygous Bernard-Soulier syndrome carrying the Bolzano-type defect. This condition prompted a systematic review of our out-patients with chronic isolated macrothrombocytopenia. We recognized that the affected members of two unrelated families represented a new variant of heterozygous Bernard-Soulier Syndrome with autosomal dominant inheritance. Sequencing analysis of the GPIb gene revealed a novel heterozygous mutation, A169C, resulting in an N41H substitution in the protein. This aminoacid belongs to the first leucine-rich repeat of the chain. The molecular modeling suggests that the replacement of the N41 with a histidine (N41H) drastically disturbs the structure of the first portion of GPIb N-terminal, directly involved in von Willebrand factor binding. As a consequence, platelet aggregation to 1.2 mg/mL of ristocetin is slightly impaired and flow cytometry reveals a reduced binding of monoclonals directed against N-terminal epitopes of the GPIb . Key words: glycoprotein Ib , Bernard-Soulier, congenital thrombocytopenia.