title: Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia.
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.
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Mi-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Seon-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Hyoung-Doo
authors.initials: HD
authors.lastname: Lee
authors.forename: Kyu-Yong
authors.initials: KY
authors.lastname: Lee
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Seo
authors.forename: Jae-Bom
authors.initials: JB
authors.lastname: Lee
authors.forename: Young-Jae
authors.initials: YJ
authors.lastname: Lee
authors.forename: Suk P
authors.initials: SP
authors.lastname: Oh
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics*; D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D018387:Codon, Initiator / Q000235:genetics*; D000071063:Endoglin; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000235:genetics*; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D018387:Codon, Initiator; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II