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Clinical Chemistry 50: 2003-2011, 2004. First published September 16, 2004; 10.1373/clinchem.2004.035287
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Right arrow Molecular Diagnostics and Genetics
(Clinical Chemistry. 2004;50:2003-2011.)
© 2004 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Mutation Analysis in Spanish Patients with Hereditary Hemorrhagic Telangiectasia: Deficient Endoglin Up-regulation in Activated Monocytes

Francisco Sanz-Rodriguez1,2,2, Africa Fernandez-L.1,2, Roberto Zarrabeitia3, Alfonso Perez-Molino3, Jose R. Ramírez4, Eliecer Coto5, Carmelo Bernabeu1 and Luisa M. Botella1,a

1 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
2 Departamento de Biología y Genética, Facultad de Biología, Universidad Autonoma de Madrid, Madrid, Spain.
3 Servicio de Medicina Interna, Hospital Sierrallana, Torrelavega (Cantabria), Spain.
4 Departamento de Anatomia Patológica, Hospital Central de la Defensa, Gómez Ulla, Madrid, Spain.
5 Genética Molecular-Instituto Reina Sofia de Investigación Renal, Hospital Central de Asturias, Oviedo, Spain.

aAddress correspondence to this author at: Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu, 9, 28040 Madrid, Spain. Fax 34-915360432; e-mail cibluisa{at}cib.csic.es.

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 Curaçao 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.




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