Sanz-Rodriguez Francisco, Fernandez-L Africa, Zarrabeitia Roberto, Perez-Molino Alfonso, Ramírez Jose R, Coto Eliecer, Bernabeu Carmelo, Botella Luisa M
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Clin Chem. 2004 Nov;50(11):2003-11. doi: 10.1373/clinchem.2004.035287. Epub 2004 Sep 16.
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.
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.
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.
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.
内皮糖蛋白（ENG）或激活素受体样激酶1（ALK1）基因的突变分别导致1型和2型遗传性出血性毛细血管扩张症（HHT1和HHT2），这是一种由单倍体不足引起的显性血管发育异常。西班牙尚未对HHT患者进行正式的突变研究。
对13例根据库拉索标准诊断的西班牙HHT患者进行ENG和ALK1突变分析。由于内皮糖蛋白在单核细胞-巨噬细胞转变过程中在细胞表面上调，因此通过免疫荧光流式细胞术在系统分析中测定活化单核细胞中的内皮糖蛋白浓度。作为对照，研究了40名非HHT志愿者活化单核细胞中内皮糖蛋白的上调情况。
在两个无关家庭的8名患者中鉴定出导致HHT的突变。其中一个家庭在ENG基因的外显子4（c.511C>T；R171X）中有一个无义突变，因此该疾病被鉴定为HHT-1。另一个家庭在ALK1基因的外显子8（c.1120C>T；R374W）中有一个错义突变，因此是一个HHT2家庭。有趣的是，与对照组相比，HHT1和HHT2患者活化单核细胞中的内皮糖蛋白上调不足。相比之下，在广泛年龄范围内的对照供体中，内皮糖蛋白上调与年龄无关。在症状最严重的患者中，活化单核细胞中内皮糖蛋白上调的程度降低最为明显。
HHT1和HHT2患者活化单核细胞中的内皮糖蛋白上调受损，且在两种HHT类型中均与年龄相关。内皮糖蛋白表达可能预测HHT的临床严重程度。
