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

Title
Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia
Author
이규용
Issue Date
2011-10
Publisher
BIOMED CENTRAL LTD, 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
Citation
BMC MEDICAL GENETICS; OCT 3 2011, 12 10p.
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-beta (TGF-beta) 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.
URI
https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-12-130
ISSN
1471-2350
DOI
10.1186/1471-2350-12-130
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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