title: BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia.
abstract: Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is caused by mutations in genes involved in the transforming growth factor beta (TGF-β) signaling pathway (ENG, ACVRL1, and SMAD4). Yet, approximately 15% of individuals with clinical features of HHT do not have mutations in these genes, suggesting that there are undiscovered mutations in other genes for HHT and possibly vascular disorders with overlapping phenotypes. The genetic etiology for 191 unrelated individuals clinically suspected to have HHT was investigated with the use of exome and Sanger sequencing; these individuals had no mutations in ENG, ACVRL1, and SMAD4. Mutations in BMP9 (also known as GDF2) were identified in three unrelated probands. These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome). Analyses of the variant proteins suggested that mutations negatively affect protein processing and/or function, and a bmp9-deficient zebrafish model demonstrated that BMP9 is involved in angiogenesis. These data confirm a genetic cause of a vascular-anomaly syndrome that has phenotypic overlap with HHT.
authors: Associated Regional and University Pathologists Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84108, USA.
authors: Whitney L
authors: WL
authors: Wooderchak-Donahue
authors: Jamie
authors: J
authors: McDonald
authors: Brendan
authors: B
authors: O'Fallon
authors: Paul D
authors: PD
authors: Upton
authors: Wei
authors: W
authors: Li
authors: Beth L
authors: BL
authors: Roman
authors: Sarah
authors: S
authors: Young
authors: Parker
authors: P
authors: Plant
authors: Gyula T
authors: GT
authors: Fülöp
authors: Carmen
authors: C
authors: Langa
authors: Nicholas W
authors: NW
authors: Morrell
authors: Luisa M
authors: LM
authors: Botella
authors: Carmelo
authors: C
authors: Bernabeu
authors: David A
authors: DA
authors: Stevenson
authors: James R
authors: JR
authors: Runo
authors: Pinar
authors: P
authors: Bayrak-Toydemir
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities*; D005260:Female; D020022:Genetic Predisposition to Disease; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000235:genetics*; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000235:genetics; D013577:Syndrome; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D015027:Zebrafish / Q000235:genetics
chemical_list: C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D008024:Ligands; D016212:Transforming Growth Factor beta
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