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5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia

Kristy Damjanovich1, Carmen Langa2, Francisco J Blanco2, Jamie McDonald13, Luisa M Botella2, Carmelo Bernabeu2, Whitney Wooderchak-Donahue1, David A Stevenson4 and Pinar Bayrak-Toydemir13*

Author Affiliations

1 ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA

2 Centro de Investigaciones Biológicas, CSIC and Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain

3 Department of Pathology, University of Utah, Salt Lake City, UT, USA

4 Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

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Orphanet Journal of Rare Diseases 2011, 6:85  doi:10.1186/1750-1172-6-85

Published: 22 December 2011



Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by epistaxis, arteriovenous malformations, and telangiectases. The majority of the patients have a mutation in the coding region of the activin A receptor type II-like 1 (ACVRL1) or Endoglin (ENG) gene. However, in approximately 15% of cases, sequencing analysis and deletion/duplication testing fail to identify mutations in the coding regions of these genes. Knowing its vital role in transcription and translation control, we were prompted to investigate the 5'untranslated region (UTR) of ENG.

Methods and Results

We sequenced the 5'UTR of ENG for 154 HHT patients without mutations in ENG or ACVRL1 coding regions. We found a mutation (c.-127C > T), which is predicted to affect translation initiation and alter the reading frame of endoglin. This mutation was found in a family with linkage to the ENG, as well as in three other patients, one of which had an affected sibling with the same mutation. In vitro expression studies showed that a construct with the c.-127C > T mutation alters the translation and decreases the level of the endoglin protein. In addition, a c.-9G > A mutation was found in three patients, one of whom was homozygous for this mutation. Expression studies showed decreased protein levels suggesting that the c.-9G > A is a hypomorphic mutation.


Our results emphasize the need for the inclusion of the 5'UTR region of ENG in clinical testing for HHT.

5'UTR region; ENG; c.-127C > T; c.-9G > A; homozygous