Hereditary Haemorrhagic Telangiectasia: current views on genetics and mechanisms of disease

Salma A Abdalla ^1* and Michelle Letarte ²

¹ St Michael's Hospital, Canada
² The Hospital for Sick Children, Canada

^* To whom correspondence should be addressed. E-mail: abdallas{at}smh.toronto.on.ca.

Accepted 28 April 2005

Abstract

Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by epistaxis, telangiectases and multi-organ vascular dysplasia. The two major types of disease, HHT1 and HHT2, are due to mutations in the ENG (ENDOGLIN) and ACVRL1 genes respectively. The corresponding endoglin and ALK-1 proteins are specific endothelial receptors of the TGF-b superfamily essential for maintaining vascular integrity. A large number of mutations have been identified in ENG and ACVRL1 genes and support the haploinsufficiency model for HHT. Two more genes have recently been implicated in HHT: MADH4 gene mutated in a combined syndrome of juvenile polyposis and HHT (JPHT) and an unidentified HHT3 gene linked to chromosome 5. We summarize the current knowledge on the genetics of HHT, the pathways that link the genes responsible for HHT and the potential mechanisms underlying the pathogenesis of disease.

Keywords: ACVRL1, ALK-1, ENG, hereditary hemorrhagic telangiectasia, vascular disorders

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Omwandho, C. O.A., Konrad, L., Halis, G., Oehmke, F., Tinneberg, H.-R. (2009). Role of TGF-{beta}s in normal human endometrium and endometriosis. Hum Reprod 0: dep382v1-dep382 [Abstract] [Full Text]  
• Post, S., Smits, A. M., van den Broek, A. J., Sluijter, J. P.G., Hoefer, I. E., Janssen, B. J., Snijder, R. J., Mager, J. J., Pasterkamp, G., Mummery, C. L., Doevendans, P. A., Goumans, M.-J. (2009). Impaired recruitment of HHT-1 mononuclear cells to the ischaemic heart is due to an altered CXCR4/CD26 balance. Cardiovasc Res 0: cvp313v2-cvp313 [Abstract] [Full Text]  
• Al-Saleh, S., Mei-Zahav, M., Faughnan, M. E., MacLusky, I. B., Carpenter, S., Letarte, M., Ratjen, F. (2009). Screening for pulmonary and cerebral arteriovenous malformations in children with hereditary haemorrhagic telangiectasia. Eur Respir J 34: 875-881 [Abstract] [Full Text]  
• Twombly, V., Bangi, E., Le, V., Malnic, B., Singer, M. A., Wharton, K. A. (2009). Functional Analysis of saxophone, the Drosophila Gene Encoding the BMP Type I Receptor Ortholog of Human ALK1/ACVRL1 and ACVR1/ALK2. Genetics 183: 563-579 [Abstract] [Full Text]  
• Towler, D. A. (2009). Bone morphogenetic proteins. Blood 114: 2012-2013 [Abstract] [Full Text]  
• Bose, P., Holter, J. L., Selby, G. B. (2009). Bevacizumab in Hereditary Hemorrhagic Telangiectasia. NEJM 360: 2143-2144 [Full Text]  
• Faughnan, M. E., Granton, J. T., Young, L. H. (2009). The pulmonary vascular complications of hereditary haemorrhagic telangiectasia. Eur Respir J 33: 1186-1194 [Abstract] [Full Text]  
• Santiago-Sim, T., Mathew-Joseph, S., Pannu, H., Milewicz, D. M., Seidman, C. E., Seidman, J.G., Kim, D. H. (2009). Sequencing of TGF-{beta} Pathway Genes in Familial Cases of Intracranial Aneurysm. Stroke 40: 1604-1611 [Abstract] [Full Text]  
• Limaye, N., Boon, L. M., Vikkula, M. (2009). From germline towards somatic mutations in the pathophysiology of vascular anomalies. Hum Mol Genet 18: R65-R74 [Abstract] [Full Text]  
• Shovlin, C. L., Gibbs, J. S. R., Jackson, J. E. (2009). Management of pulmonary arteriovenous malformations in pulmonary hypertensive patients: a pressure to embolise?. ERR 18: 4-6 [Full Text]  
• Murphy, P. A., Lam, M. T. Y., Wu, X., Kim, T. N., Vartanian, S. M., Bollen, A. W., Carlson, T. R., Wang, R. A. (2008). Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice. Proc. Natl. Acad. Sci. USA 105: 10901-10906 [Abstract] [Full Text]  
• Santibanez, J. F., Blanco, F. J., Garrido-Martin, E. M., Sanz-Rodriguez, F., del Pozo, M. A., Bernabeu, C. (2008). Caveolin-1 interacts and cooperates with the transforming growth factor-{beta} type I receptor ALK1 in endothelial caveolae. Cardiovasc Res 77: 791-799 [Abstract] [Full Text]  
• Park, S. O., Lee, Y. J., Seki, T., Hong, K.-H., Fliess, N., Jiang, Z., Park, A., Wu, X., Kaartinen, V., Roman, B. L., Oh, S. P. (2008). ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 111: 633-642 [Abstract] [Full Text]  
• van Beijnum, J, van der Worp, H B, Schippers, H M, van Nieuwenhuizen, O, Kappelle, L J, Rinkel, G J E, van der Sprenkel, J W B., Klijn, C J M (2007). Familial occurrence of brain arteriovenous malformations: a systematic review. J. Neurol. Neurosurg. Psychiatry 78: 1213-1217 [Abstract] [Full Text]  
• Brouillard, P., Vikkula, M. (2007). Genetic causes of vascular malformations. Hum Mol Genet 16: R140-R149 [Abstract] [Full Text]  
• Aird, W. C. (2007). Phenotypic Heterogeneity of the Endothelium: II. Representative Vascular Beds. Circ. Res. 100: 174-190 [Abstract] [Full Text]  
• van Laake, L. W., van den Driesche, S., Post, S., Feijen, A., Jansen, M. A., Driessens, M. H., Mager, J. J., Snijder, R. J., Westermann, C. J. J., Doevendans, P. A., van Echteld, C. J. A., ten Dijke, P., Arthur, H. M., Goumans, M.-J., Lebrin, F., Mummery, C. L. (2006). Endoglin Has a Crucial Role in Blood Cell-Mediated Vascular Repair. Circulation 114: 2288-2297 [Abstract] [Full Text]  
• Prigoda, N L, Savas, S, Abdalla, S A, Piovesan, B, Rushlow, D, Vandezande, K, Zhang, E, Ozcelik, H, Gallie, B L, Letarte, M (2006). Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. J. Med. Genet. 43: 722-728 [Abstract] [Full Text]  
• Pimanda, J. E., Chan, W.Y. I., Donaldson, I. J., Bowen, M., Green, A. R., Gottgens, B. (2006). Endoglin expression in the endothelium is regulated by Fli-1, Erg, and Elf-1 acting on the promoter and a -8-kb enhancer. Blood 107: 4737-4745 [Abstract] [Full Text]  
• Fernandez-L, A., Sanz-Rodriguez, F., Blanco, F. J., Bernabeu, C., Botella, L. M. (2006). Hereditary Hemorrhagic Telangiectasia, a Vascular Dysplasia Affecting the TGF-{beta} Signaling Pathway.. Clin Med Res 4: 66-78 [Abstract] [Full Text]  
• Gu, Y., Jin, P., Zhang, L., Zhao, X., Gao, X., Ning, Y., Meng, A., Chen, Y.-G. (2006). Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood 107: 1951-1954 [Abstract] [Full Text]