Gallione C J, Scheessele E A, Reinhardt D, Duits A J, Berg J N, Westermann C J, Marchuk D A
Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Hum Genet. 2000 Jul;107(1):40-4. doi: 10.1007/s004390000326.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant bleeding disorder characterized by localized angiodysplasia. Mutations in either of two genes, endoglin or ALK-1, can cause HHT. Both genes encode putative receptors for the transforming growth factor-beta superfamily of ligands. Many mutations in each gene have been identified in HHT kindreds from around the world, and with few exceptions mutations are unique and family specific. The prevalence of HHT in the Leeward Islands of the Netherlands Antilles is possibly the highest of any geographical location. We wished to establish whether this high prevalence is due to a genetic founder effect or to multiple mutational events. HHT kindreds from the Netherlands Antilles and The Netherlands were screened for mutations in the two genes associated with HHT. Haplotype analysis of a 5-cM region on chromosome 9 flanking the endoglin gene revealed three distinct disease haplotypes in the ten Antillean families studied. Seven of these families share a splice-site mutation in exon 1 of endoglin. Two other Antillean families share a missense mutation in exon 9a of endoglin. This mutation was also found in a Dutch family that shares the same disease haplotype as the Antillean families with this mutation. Thus it appears that HHT in the Netherlands Antilles is due to a limited number of ancestral mutations in the endoglin gene, and that one of these mutations was introduced into the African slave population by a Dutch colonist. The limited scope of mutations suggests that a presymptomatic screening program for HHT would be feasible in this population.
遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传性出血性疾病，其特征为局限性血管发育异常。内皮素基因（endoglin）或激活素受体样激酶1基因（ALK-1）发生突变均可导致HHT。这两个基因均编码转化生长因子-β超家族配体的假定受体。世界各地的HHT家族中已发现每个基因都有许多突变，除少数例外，这些突变都是独特的且具有家族特异性。荷属安的列斯群岛背风群岛的HHT患病率可能是所有地理位置中最高的。我们希望确定这种高患病率是由于遗传奠基者效应还是多次突变事件所致。对来自荷属安的列斯群岛和荷兰的HHT家族进行了与HHT相关的两个基因的突变筛查。对内皮素基因侧翼9号染色体上一个5厘摩区域的单倍型分析显示，在所研究的10个安的列斯家族中有三种不同的疾病单倍型。其中7个家族在内皮素基因第1外显子上存在一个剪接位点突变。另外两个安的列斯家族在内皮素基因第9a外显子上存在一个错义突变。在一个与有此突变的安的列斯家族具有相同疾病单倍型的荷兰家族中也发现了这种突变。因此，荷属安的列斯群岛的HHT似乎是由于内皮素基因中数量有限的祖先突变所致，其中一个突变是由一名荷兰殖民者引入非洲奴隶群体的。突变范围有限表明，在该人群中开展HHT症状前筛查项目是可行的。
