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Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: Deficient endoglin up-regulation in activated monocytes

AuthorsSánz-Rodríguez, Francisco; Fernandez-Lopez, Africa ; Zarrabeitia, Roberto; Pérez-Molino, Alfonso; Ramírez, José Ramirez; Coto, Eliecer; Bernabéu, Carmelo ; Botella, Luisa María
Issue Date2004
PublisherAmerican Association for Clinical Chemistry
CitationClinical Chemistry 50(11):2003-2011(2004)
AbstractBackground: 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 Curaçao criteria. Because endoglin is upregulated 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 upregulation 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. © 2004 American Association for Clinical Chemistry.
Identifiersdoi: 10.1373/clinchem.2004.035287
issn: 0009-9147
e-issn: 1530-8561
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