BMP9 Mutations Cause a Vascular-Anomaly Syndrome with Phenotypic Overlap with Hereditary Hemorrhagic Telangiectasia

Autor: Beth L. Roman, James R. Runo, Gyula T. Fülöp, Whitney Wooderchak-Donahue, Sarah Young, Brendan D. O'Fallon, Parker Plant, Nicholas W. Morrell, David A. Stevenson, Wei Li, Jamie McDonald, Paul D. Upton, Carmen Langa, Pinar Bayrak-Toydemir, Carmelo Bernabeu, Luisa María Botella
Přispěvatelé: National Institutes of Health (US), British Heart Foundation, Ministerio de Economía y Competitividad (España), Wooderchak-Donahue, Whitney [0000-0002-9358-7466], O'Fallon, Brendan D. [0000-0001-7185-7894], Roman, Beth L. [0000-0002-1250-1705], Young, Sarah [0000-0002-8301-5106], Morrell, Nicholas W. [0000-0001-5700-9792], Botella, Luisa María [0000-0002-6310-2245], Bernabéu, Carmelo [0000-0002-1563-6162], Bayrak-Toydemir, Pinar [0000-0001-9381-2478], Wooderchak-Donahue, Whitney, O'Fallon, Brendan D., Roman, Beth L., Young, Sarah, Morrell, Nicholas W., Botella, Luisa María, Bernabéu, Carmelo, Bayrak-Toydemir, Pinar
Jazyk: angličtina
Předmět:
Proband
Male
Identification
Telangiectases
Ligands
Rasa1 mutations
Capillary
Mice
0302 clinical medicine
Transforming Growth Factor beta
Receptors
Endothelial-cells
Growth Differentiation Factor 2
Genetics(clinical)
Weber-syndrome
Exome
Genetics (clinical)
Zebrafish
Genetics
Sanger sequencing
0303 health sciences
Syndrome
Phenotype
3. Good health
Growth Differentiation Factors
symbols
Female
Telangiectasia
Hereditary Hemorrhagic
Protein Binding
Signal Transduction
Adult
Adolescent
Locus
Mutation
Missense
GDF2
Biology
Vascular anomaly
Arteriovenous malformation
03 medical and health sciences
symbols.namesake
Report
medicine
Animals
Humans
Genetic Predisposition to Disease
030304 developmental biology
ACVRL1
medicine.disease
Amino Acid Substitution
Kinase 1 alk1
Mutation
Blood Vessels
Protein Processing
Post-Translational
030217 neurology & neurosurgery
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 0002-9297
DOI: 10.1016/j.ajhg.2013.07.004
Popis: 8 p.-5 fig.-1 tab.
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.
This work was funded by the Associated Regional and University Pathologists Institute for Clinical and Experimental Pathology, a National Institutes of Health grant R01 (HL079108 to B.L.R.), a British Heart Foundation Programme grant (RG/08/002/24718 to N.W.M), and the Ministerio de Economia y Competitividad of Spain (SAF2010-19222 to C.B.).
Databáze: OpenAIRE
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