5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia

Kristy Damjanovich,Jamie Mcdonald,Pinar Bayrak-Toydemir,David A Stevenson,Carmen Langa,Luisa M Botella,Carmelo Bernabeu,Whitney Wooderchak-Donahue,Francisco J Blanco

doi:10.1186/1750-1172-6-85

Abstract

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

Highlights

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by epistaxis, arteriovenous malformations, and telangiectases
Cases listed as having no solid organ involvement had screening for pulmonary arteriovenous malformations (AVMs) (PAVMs) by contrast echocardiogram and/or chest computed tomography (CT) and for brain AVMs by a contrasted magnetic resonance imaging (MRI), and physical examination and medical history that did not suggest other AVMs
The number of PAVMs observed in these families with c.-127C > T mutation seems possibly greater than typical for HHT1 disease, this may represent ascertainment bias since the majority of these patients were seen in an HHT specialty clinic that tend to attract patients with pulmonary AVMs for treatment and expected variation of HHT

Summary

Introduction

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. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by epistaxis, telangiectasesand arteriovenous malformations (AVMs). The majority of the clinically diagnosed HHT patients have a mutation in the coding regions of the Endoglin (ENG) gene or activin A receptor type II-like 1 (ACVRL1) gene [9,10,11,12,13,14,15], leading to HHT1 or HHT2, respectively. At least two additional genes, at 5q31.3-32 (HHT3) [17] and 7p14 (HHT4) [18], have been suggested by linkage studies

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