title: Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: deficient endoglin up-regulation in activated monocytes.
abstract: BACKGROUND
  Mutations in the endoglin (ENG) or ALK1 genes are responsible for hereditary hemorrhagic telangiectasia types 1 and 2 (HHT1 and HHT2), respectively, a dominant vascular dysplasia caused by haploinsufficiency. No formal mutation studies of patients with HHT have been conducted in Spain.
  
  
  METHODS
  ENG and ALK1 mutation analyses were carried out in 13 Spanish HHT patients diagnosed according to the Curacao criteria. Because endoglin is up-regulated at the cell surface during the monocyte-macrophage transition, endoglin concentrations in activated monocytes were determined by immunofluorescence flow cytometry in a systematic analysis. As controls, 40 non-HHT volunteers were studied for up-regulation of endoglin in activated monocytes.
  
  
  RESULTS
  The mutation responsible for HHT was identified in eight patients belonging to two unrelated families. One of the families has a nonsense mutation in exon 4 (c.511C>T; R171X) of the ENG gene, and accordingly the disorder was identified as HHT1. The other family has a missense mutation affecting exon 8 (c.1120C>T; R374W) of the ALK1 gene, and hence is a HHT2 family. Interestingly, endoglin up-regulation was deficient in activated monocytes of both HHT1 and HHT2 patients compared with controls. By contrast, endoglin up-regulation was age-independent in control donors across a broad range of ages. The extent of endoglin up-regulation in activated monocytes was most diminished in those patients with the most severe symptoms.
  
  
  CONCLUSIONS
  Endoglin up-regulation in activated monocytes is impaired in HHT1 and HHT2 patients and is age-dependent in both HHT types. Endoglin expression may predict the clinical severity of HHT.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sanz-Rodriguez
authors.forename: Africa
authors.initials: A
authors.lastname: Fernandez-L
authors.forename: Roberto
authors.initials: R
authors.lastname: Zarrabeitia
authors.forename: Alfonso
authors.initials: A
authors.lastname: Perez-Molino
authors.forename: Jose R
authors.initials: JR
authors.lastname: Ramírez
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabeu
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Botella
mesh_terms: D015703:Antigens, CD; D000071063:Endoglin; D005434:Flow Cytometry; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation; D011956:Receptors, Cell Surface; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013030:Spain; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000097:blood / Q000235:genetics*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1