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Human Molecular Genetics Advance Access originally published online on April 9, 2007
Human Molecular Genetics 2007 16(13):1515-1533; doi:10.1093/hmg/ddm069
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Gene expression fingerprinting for human hereditary hemorrhagic telangiectasia

Africa Fernandez-Lopez1,2, Eva M. Garrido-Martin1,2, Francisco Sanz-Rodriguez3, Miguel Pericacho4, Alicia Rodriguez-Barbero4, Nelida Eleno4, Jose M. Lopez-Novoa4, Anette Düwell4, Miguel A. Vega1, Carmelo Bernabeu1,2 and Luisa M. Botella1,2,*

1 Centro de Investigaciones Biológicas, CSIC, Madrid, Spain, 2 Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain, 3 Facultad de Biología, Universidad Autónoma de Madrid, Madrid, Spain and 4 Instituto ‘Reina Sofía’ de Investigacion Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain

* To whom correspondence should be addressed at:, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu, 9, 28040 Madrid, Spain. Tel: +34 918373112 ext. 4312; Fax: +34 915360432; Email: cibluisa{at}cib.csic.es

Received January 17, 2007; Revised March 5, 2007; Accepted March 16, 2007

Hereditary hemorrhagic telangiectasia (HHT) or Osler–Weber–Rendu syndrome is an autosomal dominant vascular disorder characterized by telangiectases and internal arteriovenous malformations. It is caused by mutations in elements of the transforming growth factor-ß (TGF-ß) receptor complex: endoglin, a co-receptor, responsible for HHT1, or ALK1 (activin receptor-like kinase 1), a type I receptor leading to HHT2. Recently, we have established cultures of HHT endothelial cells, primary targets of the disease. These cells showed deficient TGF-ß signaling and angiogenesis, representing a useful human model to study the molecular mechanism of this disease. To understand the pathogenic mechanism underlying HHT, we have used total RNA probes to compare HHT versus non-HHT cells by expression microarrays. This work represents a systematic study to identify target genes affected in HHT cells. Given the similarity of symptoms in HHT1 and HHT2, special interest has been put on the identification of common targets for both HHT types. As a result, 277 downregulated and 63 upregulated genes were identified in HHT versus control cells. These genes are involved in biological processes relevant to the HHT pathology, such as angiogenesis, cytoskeleton, cell migration, proliferation and NO synthesis. The type of misregulated genes found in HHT endothelial cells lead us to propose a model of HHT pathogenesis, opening new perspectives to understand this disorder. Moreover, as the disease is originated by mutations in proteins of the TGF-ß receptor complex, these results may be useful to find out targets of the TGF-ß pathway in endothelium.


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