Brusgaard K, Kjeldsen A D, Poulsen L, Moss H, Vase P, Rasmussen K, Kruse T A, Hørder M
Department of Clinical Biochemistry and Molecular Genetics, Odense University Hospital, Odense C, Denmark.
Clin Genet. 2004 Dec;66(6):556-61. doi: 10.1111/j.1399-0004.2004.00341.x.
Hereditary haemorrhagic telangiectasia (HHT) is a rare disorder with one per 6000-10,000 affected individuals in the general Caucasian population. HHT is genetically heterogeneous, involving at least two loci HHT1 mapping to chromosome 9q34.1 and HHT2 mapping to chromosome 12q31. The loci have been identified as endoglin (ENG) and activin receptor-like kinase 1 (ALK1). In order to gain knowledge of the genotype distribution and prevalence in the Danish population and to establish a reproducible and sensitive molecular genetic test method, we developed a denaturating gradient gel electrophoresis protocol for mutation scanning of the two loci. Twenty-five Danish HHT families were tested. A total of eight new as well as seven previously reported mutations were identified. A founder mutation was characterized present in seven families and possibly introduced around 350 years ago. In one individual, a presumed spontaneous mutation was characterized. The method developed proved to be very sensitive for mutation detection in both ENG and ALK1. Genetic screening in HHT families facilitates an early treatment strategy for silent HHT manifestations in first degree relatives.
遗传性出血性毛细血管扩张症（HHT）是一种罕见疾病，在普通白种人群中，每6000 - 10000人中有一人患病。HHT具有遗传异质性，至少涉及两个基因座，HHT1定位于9号染色体q34.1，HHT2定位于12号染色体q31。这些基因座已被确定为内皮素（ENG）和激活素受体样激酶1（ALK1）。为了了解丹麦人群中的基因型分布和患病率，并建立一种可重复且敏感的分子遗传学检测方法，我们开发了一种用于这两个基因座突变扫描的变性梯度凝胶电泳方案。对25个丹麦HHT家庭进行了检测。共鉴定出8个新突变以及7个先前报道的突变。在7个家庭中发现了一个奠基者突变，可能是在约350年前引入的。在一个个体中，鉴定出一个推测的自发突变。所开发的方法被证明对ENG和ALK1中的突变检测非常敏感。对HHT家庭进行基因筛查有助于为一级亲属中无症状的HHT表现制定早期治疗策略。
