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.

Rapid Activation of Bone Morphogenic Protein 9 by Receptor-mediated Displacement of Pro-domains

“…In addition to the described physiological implications of our findings, the displacement of the pro-domains is of significant translational interest for ELISA measurement of BMP9 circulating variants, a method that may be important for present and future research regarding BMP9. Recently, GDF2 (encoding BMP9) mutations have been described in three unrelated individuals presenting with a vascular anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia (8). The mutations occurred within the pro-domain and the mature peptide and were associated with a defect in BMP9 processing.…”

“…Human mutations in ALK1 lead to a genetic vascular disorder known as hereditary hemorrhagic telangiectasia (7). Recently, mutations in BMP9 have been identified in individuals with a vascular disorder phenotypically overlapping with hereditary hemorrhagic telangiectasia (8). BMP9 was also discovered to function as a neurotropic factor, potently inducing and maintaining the cholinergic phenotype in the central nervous system (9), and is also the most potent BMP for inducing osteogenic, and to a lesser extent adipogenic and chondrogenic differentiation (10,11).…”

BMP-9 balances endothelial cell fate

“…HHT can be caused by mutations in other ALK-1 pathway components, including the ALK-1 coreceptor endoglin that aids ligand binding, and Smad4, which partners with TGF-β-and BMP-activated Smads (25). Recently, causative BMP9 missense mutations have been implicated in an HHT-related syndrome (26). Thus, HHTcausing mutations appear to define a BMP-9-endoglin-ALK-1-Smad4 pathway.…”

Structure of bone morphogenetic protein 9 procomplex

“…Although a member of the BMP subfamily and possessing chondrogenic and osteogenic activity, BMP9 is expressed in liver and is required for properly organized blood and lymphatic vascular development (11,12). Mutations in the prodomain of BMP9, in its receptor Alk1, and in its coreceptor endoglin cause phenotypically overlapping hereditary hemorrhagic telangiectasias (13)(14)(15).…”