title: 5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our results emphasize the need for the inclusion of the 5'UTR region of ENG in clinical testing for HHT.
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Damjanovich
authors.forename: Carmen
authors.initials: C
authors.lastname: Langa
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Blanco
authors.forename: Jamie
authors.initials: J
authors.lastname: McDonald
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Botella
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabeu
authors.forename: Whitney
authors.initials: W
authors.lastname: Wooderchak-Donahue
authors.forename: David A
authors.initials: DA
authors.lastname: Stevenson
authors.forename: Pinar
authors.initials: P
authors.lastname: Bayrak-Toydemir
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D000071063:Endoglin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics*; D014162:Transfection
chemical_list: D020121:5' Untranslated Regions; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface