title: Identification of the integrin β3 L718P mutation in a pedigree with autosomal dominant thrombocytopenia with anisocytosis.
abstract: αIIbβ3 integrin mutations that result in the complete loss of expression of this molecule on the platelet surface cause Glanzmann thrombasthenia. This is usually autosomal recessive, while other mutations are known to cause dominantly inherited macrothrombocytopenia (although such cases are rare). Here, we report a 4-generation pedigree including 10 individuals affected by dominantly inherited thrombocytopenia with anisocytosis. Six individuals, whose detailed clinical and laboratory data were available, carried a non-synonymous ITGB3 gene alteration resulting in mutated integrin β3 (ITGB3)-L718P. This mutation causes partial activation of the αIIbβ3 complex, which promotes the generation of abnormal pro-platelet-like protrusions through downregulating RhoA (RHOA) activity in transfected Chinese Hamster Ovary cells. These findings suggest a model whereby the integrin β3-L718P mutation contributes to thrombocytopenia through gain-of-function mechanisms.
authors.affiliation: Department of Molecular Oncology and Leukaemia Programme Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsui
authors.forename: Akinori
authors.initials: A
authors.lastname: Kanai
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tsumura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.forename: Mizuka
authors.initials: M
authors.lastname: Miki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D015536:Down-Regulation; D004913:Erythrocytes, Abnormal / Q000502:physiology*; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000502:physiology
chemical_list: D039661:Integrin beta3; D020742:rhoA GTP-Binding Protein