title: Novel point mutation in a leucine-rich repeat of the GPIbalpha 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.
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 GPIbalpha 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 GPIbalpha 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 GPIbalpha.
authors.affiliation: Chair of Internal Medicine, Department of Medical and Surgical Sciences, via Giustiniani 1, 35128 Padova, Italy., fabrizio.fabris@unipd.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vettore
authors.forename: Raffaella
authors.initials: R
authors.lastname: Scandellari
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Lombardi
authors.forename: Margherita
authors.initials: M
authors.lastname: Scapin
authors.forename: Maria Luigia
authors.initials: ML
authors.lastname: Randi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fabris
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001606:Bernard-Soulier Syndrome / Q000097:blood / Q000235:genetics*; D001792:Blood Platelets / Q000473:pathology / Q000502:physiology; D016384:Consensus Sequence; D017124:Conserved Sequence; D005190:Family; D005260:Female; D005434:Flow Cytometry; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins / Q000235:genetics*; D017354:Point Mutation
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; C094990:adhesion receptor; C028254:von Willebrand factor receptor