Olivieri Carla, Pagella Fabio, Semino Lucia, Lanzarini Luca, Valacca Cristina, Pilotto Andrea, Corno Sabrina, Scappaticci Susi, Manfredi Guido, Buscarini Elisabetta, Danesino Cesare
Biologia Generale e Genetica Medica, University of Pavia, Via Forlanini, 14, 27100, Pavia, Italy.
Clinica Otorinolaringoiatrica, Fondazione IRCCS Policlinico "S. Matteo", Pavia, Italy.
J Hum Genet. 2007;52(10):820-829. doi: 10.1007/s10038-007-0187-5. Epub 2007 Sep 5.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder causing vascular dysplasias. About 70-80% of HHT patients carries mutations in ENG or ACVRL1 genes, which code for a TGFbeta receptor type III and I respectively. Molecular data on a large cohort of Italian HHT patients are presented, discussing the significance of missense and splice site mutations. Mutation analysis in ENG and ACVRL1 genes was performed using single strand conformation polymorphisms (SSCP), denaturing high performance liquid chromatography (DHPLC) and subsequent direct sequencing. Overall, 101 mutations were found, with ACVRL1 involved in 71% of cases. The highest number of mutations (28/101 subjects, 14/76 different mutations referring to both genes) was in ACVRL1, exon 3. Mutation analysis was then extended to a total of 356 family members, and 162 proven to carry the mutation. New polymorphisms were identified in both genes, and evidence that ENG P131L change is not a disease-causing mutation was also provided. An in silico analysis was performed in order to characterize splice-site mutations. These results were compared to other European national studies and data from Italy, France and Spain were consistent for an higher incidence of ACVRL1 mutations.
遗传性出血性毛细血管扩张症（HHT）是一种导致血管发育异常的常染色体显性疾病。约70-80%的HHT患者携带ENG或ACVRL1基因突变，这两个基因分别编码III型和I型转化生长因子β受体。本文展示了一大组意大利HHT患者的分子数据，讨论了错义突变和剪接位点突变的意义。使用单链构象多态性（SSCP）、变性高效液相色谱（DHPLC）及随后的直接测序对ENG和ACVRL1基因进行突变分析。总体而言，共发现101个突变，其中71%的病例涉及ACVRL1基因。突变数量最多的是ACVRL1基因的第3外显子（28/101例受试者，76个不同突变中有14个涉及这两个基因）。随后对总共356名家庭成员进行了突变分析，其中162人被证实携带该突变。在两个基因中均鉴定出了新的多态性，同时也提供了证据表明ENG基因的P131L改变并非致病突变。进行了计算机分析以表征剪接位点突变。将这些结果与其他欧洲国家的研究进行比较，来自意大利、法国和西班牙的数据一致表明ACVRL1基因突变的发生率较高。
