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

Abstract

BackgroundHereditary 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.MethodsThree 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.ResultsTwo 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.ConclusionsThis 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.

Characterization of a family mutation in the 5’ untranslated region of the endoglin gene causative of hereditary hemorrhagic telangiectasia

“…These findings clearly suggest that non-coding regions may also play a role in the disease. In fact, several reports have described the existence of HHT causing mutations in the 5'UTR and introns of ENG [http://arup.utah.edu/database/ ENG/ENG_display.php; [16,17,[19][20][21]. Among these are variants that involve the 400-bp upstream from the TIS of ENG, a region near the transcription initiation site and essential for ENG promoter function [18].…”

“…Studies in some of these families have revealed the existence of mutations in non-coding DNA sequences such as introns or regulatory regions of ENG [http://arup.utah.edu/database/ENG/ENG_display.php; [16,17]. In this sense, mutations in the 5'UTR of ENG [18] may account for the pathogenesis of HHT in some patients [19][20][21]. Supporting the critical regulatory role of this region is the fact that most of the protein complexes involved in transcription and/or translation bind and regulate expression from the 5'UTR of the gene.…”

National mutation study among Danish patients with hereditary haemorrhagic telangiectasia

“…No mutation was identified in 12 probands, which can be explained in different ways. Mutations may reside outside the coding sequence, in introns, in the promoter , or in other regulatory regions. As linkage analysis has already pointed out also other, yet unidentified, genes could be responsible for the HHT phenotype in some families.…”

Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1

“…Mutations range from single base-pair changes to major deletions of multiple exons. Recently, pathogenic mutations affecting the 5’ UTR region of ENG leading to new translation initiation sites (TIS) dominant over the normal endoglin TIS have also been described [ 20 , 21 ].…”