Lesca Gaëtan, Plauchu Henri, Coulet Florence, Lefebvre Sylvain, Plessis Ghislaine, Odent Sylvie, Rivière Sophie, Leheup Bruno, Goizet Cyril, Carette Marie-France, Cordier Jean-François, Pinson Stéphane, Soubrier Florent, Calender Alain, Giraud Sophie
Laboratoire de Génétique, Hôpital Edouard Herriot, Lyon, France.
Hum Mutat. 2004 Apr;23(4):289-99. doi: 10.1002/humu.20017.
Hereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an autosomal dominant disease characterized by arteriovenous malformations, affecting 1 out of 10,000 individuals in France. The disease is caused by mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of ENG and ALK1 in 160 unrelated French index cases. A germline mutation was identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG, including three nonsense mutations, 19 small insertions/deletions leading to a frameshift, two inframe deletions, seven missense mutations, and five intronic or splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of 64 mutations were found in ALK1, including six nonsense mutations, 28 small insertions/deletions leading to a frameshift, one inframe deletion, 27 missense mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27 were novel mutations. Mutations were found in most parts of the coding sequence for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5, c.1103+3_1103+8del activated a cryptic splice site 22 bp upstream, and c.1428G>A produced two abnormal transcripts, one including intron 11 and the other excluding exon 10. Although most of the mutations were private, some recurrent mutations in ALK1 were of particular interest. Mutation c.1112_1113dupG (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common haplotype, strongly suggesting a founder effect related to the concentration of patients previously reported in a specific French region (Rhône-Alpes). Three missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot.
遗传性出血性毛细血管扩张症（HHT，又称奥斯勒-伦杜-韦伯综合征）是一种常染色体显性疾病，其特征为动静脉畸形，在法国每10000人中就有1人患病。该疾病由两个基因ENG和ALK1（ACVRL1）的突变引起。我们对160例无亲缘关系的法国索引病例的ENG和ALK1编码序列进行了筛查。在100名个体（62.5%）中鉴定出种系突变。ENG基因共发现36个突变，包括3个无义突变、19个导致移码的小插入/缺失、2个框内缺失、7个错义突变以及5个内含子或剪接位点突变。在这36个突变中，有33个是新突变。ALK1基因共发现64个突变，包括6个无义突变、28个导致移码的小插入/缺失、1个框内缺失、27个错义突变以及2个内含子或剪接位点突变。在这64个突变中，有27个是新突变。两个基因的编码序列大部分区域都发现了突变，但ALK1基因的第5外显子和ENG基因的第12至14外显子除外。ALK1基因的错义突变在第7、8和10外显子中更为常见。对ENG基因的三个内含子突变进行了cDNA测序：c.689+2T>C产生了一个不包括第5外显子的异常转录本，c.1103+3_1103+8del激活了上游22 bp处的一个隐蔽剪接位点，c.1428G>A产生了两个异常转录本，一个包括第11内含子另一个不包括第10外显子。虽然大多数突变是散发性的，但ALK1基因中的一些复发性突变特别令人关注。在17名共享一个常见单倍型的无亲缘关系个体中发现了突变c.1112_1113dupG（p.Gly371fsX391），这强烈表明存在与先前报道的法国特定地区（罗纳-阿尔卑斯）患者集中情况相关的奠基者效应。三个错义突变涉及同一个密码子：c.1231C>T（p.Arg411Trp）、c.1232G>C（p.Arg411Pro）和c.1232G>A（p.Arg411Gln）分别在7名、2名和1名患者中被发现。单倍型分析支持存在奠基者效应和突变热点。
