title: Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function.
abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inheritable vascular dysplasia caused by mutations in genes encoding either endoglin or activin receptor-like kinase-1 (ALK1). Functional significance of endoglin missense mutations remains largely unknown leading to a difficult discrimination between polymorphisms and pathogenic mutations. In order to study the functional significance of endoglin mutations and to help HHT1 diagnosis, we developed a cellular assay based on the ability of endoglin to enhance ALK1 response to bone morphogenetic protein 9 (BMP9). We generated and characterized 31 distinct ENG mutants reproducing human HHT1 missense mutations identified in patients of the Molecular Genetics Department in Lyon. We found that 16 mutants behaved like wild-type (WT) endoglin, and thus corresponded to benign rare variants. The 15 other variants showed defects in BMP9 response and were identified as pathogenic mutations. Interestingly, two mutants (S278P and F282V) had lost their ability to bind BMP9, identifying two crucial amino acids for BMP9 binding to endoglin. For all the others, the functional defect was correlated with a defective trafficking to the cell surface associated with retention in the endoplasmic reticulum. Further, we demonstrated that some intracellular mutants dimerized with WT endoglin and impaired its cell-surface expression thus acting as dominant-negatives. Taken together, we show that endoglin loss-of-function can result from different mechanisms in HHT1 patients. We also provide a diagnostic tool helping geneticists in screening for novel or conflicting ENG mutations.
authors.affiliation: Inserm, U1036, Grenoble F-38000, France, CEA, DSV, iRTSV, Laboratoire Biologie du Cancer et de L'Infection, Grenoble F-38000, France, University Grenoble-Alpes, Grenoble F-38000, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Mallet
authors.affiliation: Inserm, U1036, Grenoble F-38000, France, CEA, DSV, iRTSV, Laboratoire Biologie du Cancer et de L'Infection, Grenoble F-38000, France, University Grenoble-Alpes, Grenoble F-38000, France.
authors.forename: Khadija
authors.initials: K
authors.lastname: Lamribet
authors.affiliation: Hôpital Edouard Herriot Service de Génétique Moléculaire et Clinique, Lyon, France and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.affiliation: Hospices Civils de Lyon, Hôpital Louis Pradel, Genetic Department and National Reference Center for Rendu-Osler Disease, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupuis-Girod
authors.affiliation: Inserm, U1036, Grenoble F-38000, France, CEA, DSV, iRTSV, Laboratoire Biologie du Cancer et de L'Infection, Grenoble F-38000, France, University Grenoble-Alpes, Grenoble F-38000, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.affiliation: Inserm, U1036, Grenoble F-38000, France, CEA, DSV, iRTSV, Laboratoire Biologie du Cancer et de L'Infection, Grenoble F-38000, France, University Grenoble-Alpes, Grenoble F-38000, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bailly
authors.affiliation: Inserm, U1036, Grenoble F-38000, France, CEA, DSV, iRTSV, Laboratoire Biologie du Cancer et de L'Infection, Grenoble F-38000, France, University Grenoble-Alpes, Grenoble F-38000, France, emmanuelle.tillet@cea.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tillet
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000071063:Endoglin; D015870:Gene Expression; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D011956:Receptors, Cell Surface