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Open Access Highly Accessed Research article

Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia

Mi-Jung Kim12, Seon-Tae Kim3, Hyoung-Doo Lee4, Kyu-Yong Lee5, Jiyoung Seo1, Jae-Bom Lee16, Young-Jae Lee1* and Suk P Oh127*

Author Affiliations

1 Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea

2 World Class University Program, Gachon University, Incheon, Korea

3 Department of Otolaryngology, School of Medicine, Gachon University, Incheon, Korea

4 Department of Pediatrics, Pusan National University College of Medicine, Pusan, Korea

5 Department of Neurology, Hanyang University College of Medicine, Seoul, Korea

6 Department of Life Science, Hallym University, Chuncheon, Korea

7 Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA

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BMC Medical Genetics 2011, 12:130  doi:10.1186/1471-2350-12-130

Published: 3 October 2011

Abstract

Background

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder, characterized by recurrent epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVMs) in various visceral organs. Endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1; ALK1), receptors for transforming growth factor-β (TGF-β) superfamily, have been identified as the principal HHT-causing genes.

Methods

Three unrelated Korean HHT patients and their asymptomatic as well as symptomatic family members were genetically diagnosed by sequencing whole exons and their flanking regions of ENG and ACVRL1. Functionality of an aberrant translation start codon, which is created by a substitution mutation at the 5'-untranslated region (UTR) of ENG found in a HHT family, was tested by transient in vitro transfection assay. Decay of the mutant transcripts was also assessed by allele-specific expression analysis.

Results

Two ENG and one ACVRL1 mutations were identified: a known ENG mutation (c.360+1G > A; p.Gly74_Tyr120del); a novel ENG mutation (c.1-127C > T); and a novel ACVRL1 mutation (c.252_253insC; p.Val85fsX168). We further validated that the 5'-UTR ENG mutation prevents translation of ENG from the biological translation initiation site of the mutant allele, and leads to degradation of the mutant transcripts.

Conclusions

This is the first experimental demonstration that a 5'-UTR mutation can prevent translation of ENG among HHT patients, and further supports the previous notion that haploinsufficiency is the primary mechanism of HHT1. Our data also underscore the importance of including exons encoding 5' UTR for HHT mutation screening.