Received on April 6, 2004
Accepted on August 27, 2004

Molecular Diagnostics and Genetics

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

¹ Centro de Investigaciones Biológicas, CSIC, Madrid, Spain, and Departamento de Biología y Genética, Facultad de Biología, Universidad Autonoma de Madrid, Madrid, Spain
² Centro de Investigaciones Biológicas, CSIC, 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-IRSIN, Hospital Central de Asturias, Oviedo, Spain

^* To whom correspondence should be addressed. 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 has 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.