遗传性出血性毛细血管扩张症的研究进展

本文对遗传性出血性毛细血管扩张症（Hereditary hemorrhagic telangiectasia，HHT）及其研究进展进行了较全面地论述。HHT是常染色体显性遗传性血管发育异常的一种疾病。目前发现该病的致病基因有2个,一个是Endoglin（ENG）基因，该基因被定位于9q34．1。ENG基因全长约40kb，由14个外显子构成，其编码endodin（ENG）蛋白，主要表达在内皮细胞上。由ENG基因突变所引起的HHT称为HHT1。以后研究又发现．引起HHT的另一个原因是activin receptor-like kinase 1（ALK-1）基因突变所致，ALK-1基因被定位于12q11-q14。ALK-1基因全长约14kb，由10个外显子构成，其编码ALK-1蛋白，其主要表达在内皮细胞上。由ALK-1基因突变所引起的HHT称为HHT2。目前发现与HHT有关的不同的突变有129个，其中有79个与ENG基因突变有关，50个与ALK-1基因突变有关。ENG基因或ALK-1基因的突变有错义突变、无义突变、剪接点突变。目前研究认为HHT产生的分子机制是单倍不足（haploinsufficiency）或显性失活（dominant negative）。据目前的研究资料．尚未发现突变热点。HHT1与HHT2相比，HHT1的表型更为严重。

Advance of research on hereditary hemorrhagic telangiectasia

This articl expatiates in more detail on hereditary hemorrhagic telangiectasia(HHT) and its advance of research. HHT is an autosomal dominant disordercharacterized by vascular dysplasia. HHT is caused by a mutation either in the endoglin (ENG) gene or the activin receptor-like kinase 1(ALK-1) gene. ENG gene maps to chromosome 9q34.1, and contains 14 exons and spans approxinmately 40 kb of genomic DNA. ENG is expressed primarily in vascular endothelial cells. Mutation of ENG gene can cause type 1 hereditary hemorrhagic telangiectasia(HHT1). Mutation of ALK-1 gene can cause type 2 hereditary hemorrhagic telangiectasia(HHT2). ALK-1 gene maps to chromosome 12q11-q14, and contains 10 exons and spans approxinmately 14 kb of genomic DNA.ALK-1 is most highly expressed in endothelial cells. About 129 different HHT-related mutations have been reported so far, 79 in ENG and 50 in ALK-1, including missense, nonsense, frameshift, splice-site. Current data suggests that HHT molecular mechanism caused by mutation is haploinsufficiency or dominant negative. There appear to be no mutational hot spots in these two genes. HHT1 has a more severe phenotype than HHT2.