title: A novel ENG mutation causing impaired co-translational processing of endoglin associated with hereditary hemorrhagic telangiectasia.
abstract: Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal dominant vascular dysplasia caused by mutations in mainly the endoglin gene (ENG) or activin-like kinase receptor 1 (ALK1) gene (ACVRL1). We investigated the molecular basis of HHT in a Japanese patient, and identified a novel missense mutation in ENG (c.38T>A, p.Leu13Gln) located in the signal peptide's hydrophobic core, but not in ACVRL1. In experiments in COS-1 cells, the Leu13Gln (L13Q) mutant endoglin appeared to be expressed as a precursor form, probably due to impaired protein processing. Flow cytometry analyses of the COS-1 cells transiently expressing recombinant endoglins revealed that the wild-type endoglin was detected on the cell surface, but the L13Q mutant was not. We also analyzed expression patterns of the recombinant endoglins by immunofluorescent staining, and found that the wild-type co-localized with the endoplasmic reticulum (ER), but the L13Q mutant did not. These results implied that the L13Q mutant endoglin fails to insert into the ER, probably due to destruction of the hydrophobic core structure in the signal peptide to be recognized by signal recognition particles. Thus, the Leu13 in the signal peptide of endoglin might be essential for correct protein processing through the ER and cell-surface expression. Taken together, the novel c.38T>A mutation in ENG would impair co-translational processing of the endoglin, and could be responsible for HHT in this patient.
authors.affiliation: Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-Ku, Nagoya 461-8673, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Suzuki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakashima
authors.forename: Yuhri
authors.initials: Y
authors.lastname: Miyawaki
authors.forename: Junko
authors.initials: J
authors.lastname: Fujita
authors.forename: Asuka
authors.initials: A
authors.lastname: Maki
authors.forename: Yuta
authors.initials: Y
authors.lastname: Fujimori
authors.forename: Akira
authors.initials: A
authors.lastname: Takagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Murate
authors.forename: Masaaki
authors.initials: M
authors.lastname: Teranishi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Saito
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Kojima
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D000071063:Endoglin; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface