SMAD4 mutations found in unselected HHT patients
SMAD4 mutations found in unselected HHT patients
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DOI：
10.1136/jmg.2006.041517
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发表时间：
2006-10-01
影响因子：
4
通讯作者：
Marchuk, D. A.
中科院分区：
文献类型：
--
作者：
Gallione, C. J.;Richards, J. A.;Marchuk, D. A.
背景：遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性疾病，表现为多灶性血管毛细血管扩张和动静脉畸形。大多数病例是由内皮糖蛋白 (ENG) 或激活素受体样激酶 1 (ALK1、ACVRL1) 基因突变引起；两者都是转化生长因子 (TGF)-β 途径的成员。 SMAD4（另一种 TGF-β 通路成员）的突变常见于幼年性息肉病 (JP) 和 HHT 联合综合征 (JP-HHT) 的患者。方法：我们试图确定没有任何明显 JP 病史且正在接受常规诊断检测的 HHT 患者是否存在 SMAD4 突变。我们测试了 30 名无关的 HHT 患者，他们都被转诊进行基于 DNA 的 HHT 检测，结果发现 ENG 和 ALK1 突变呈阴性。 结果：其中 3 人携带 SMAD4 突变，比率为 10% (3/30)。 SMAD4 突变与其他 JP-HHT 综合征患者中发现的突变相似。结论：在未事先诊断为 JP 的 HHT 患者中鉴定 SMAD4 突变具有显着且直接的临床意义，因为这些人可能有患 JP-HHT 的风险，并伴有胃肠道癌风险增加。我们建议，针对 HHT 的常规 DNA 检测应包括 SMAD4，用于检测 ENG 和 ALK1 均未发现突变的样本。具有 SMAD4 突变的 HHT 患者应筛查与 JP 相关的结肠和胃息肉。
Background: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease exhibiting multifocal vascular telangiectases and arteriovenous malformations. The majority of cases are caused by mutations in either the endoglin (ENG) or activin receptor-like kinase 1 (ALK1, ACVRL1) genes; both members of the transforming growth factor (TGF)-beta pathway. Mutations in SMAD4, another TGF-beta pathway member, are seen in patients with the combined syndrome of juvenile polyposis (JP) and HHT (JP-HHT).Methods: We sought to determine if HHT patients without any apparent history of JP, who were undergoing routine diagnostic testing, would have mutations in SMAD4. We tested 30 unrelated HHT patients, all of whom had been referred for DNA based testing for HHT and were found to be negative for mutations in ENG and ALK1.Results: Three of these people harboured mutations in SMAD4, a rate of 10% (3/30). The SMAD4 mutations were similar to those found in other patients with the JP-HHT syndrome.Conclusions: The identification of SMAD4 mutations in HHT patients without prior diagnosis of JP has significant and immediate clinical implications, as these people are likely to be at risk of having JP-HHT with the associated increased risk of gastrointestinal cancer. We propose that routine DNA based testing for HHT should include SMAD4 for samples in which mutations in neither ENG nor ALK1 are identified. HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps associated with JP.