Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco San Francisco, CA, USA ; Department of Medical Genetics, University Medical Centre Utrecht Utrecht, Netherlands.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco San Francisco, CA, USA.
Front Genet. 2015 Mar 12;6:67. doi: 10.3389/fgene.2015.00067. eCollection 2015.
HHT shows clinical variability within and between families. Organ site and prevalence of arteriovenous malformations (AVMs) depend on the HHT causative gene and on environmental and genetic modifiers. We tested whether variation in the functional ENG allele, inherited from the unaffected parent, alters risk for pulmonary AVM in HHT1 mutation carriers who are ENG haploinsufficient. Genetic association was found between rs10987746 of the wild type ENG allele and presence of pulmonary AVM [relative risk = 1.3 (1.0018-1.7424)]. The rs10987746-C at-risk allele associated with lower expression of ENG RNA in a panel of human lymphoblastoid cell lines (P = 0.004). Moreover, in angiogenically active human lung adenocarcinoma tissue, but not in uninvolved quiescent lung, rs10987746-C was correlated with expression of PTPN14 (P = 0.004), another modifier of HHT. Quantitative TAQMAN expression analysis in a panel of normal lung tissues from 69 genetically heterogeneous inter-specific backcross mice, demonstrated strong correlation between expression levels of Eng, Acvrl1, and Ptpn14 (r2 = 0.75-0.9, P < 1 × 10(-12)), further suggesting a direct or indirect interaction between these three genes in lung in vivo. Our data indicate that genetic variation within the single functional ENG gene influences quantitative and/or qualitative differences in ENG expression that contribute to risk of pulmonary AVM in HHT1, and provide correlative support for PTPN14 involvement in endoglin/ALK1 lung biology in vivo. PTPN14 has been shown to be a negative regulator of Yap/Taz signaling, which is implicated in mechanotransduction, providing a possible molecular link between endoglin/ALK1 signaling and mechanical stress. EMILIN2, which showed suggestive genetic association with pulmonary AVM, is also reported to interact with Taz in angiogenesis. Elucidation of the molecular mechanisms regulating these interactions in endothelial cells may ultimately provide more rational choices for HHT therapy.
HHT 表现出家族内和家族间的临床变异性。器官部位和动静脉畸形 (AVM) 的患病率取决于 HHT 的致病基因以及环境和遗传修饰因子。我们测试了从未受影响的父母那里遗传的功能性 ENG 等位基因的变异是否会改变 ENG 单倍不足的 HHT1 突变携带者发生肺 AVM 的风险。在野生型 ENG 等位基因的 rs10987746 与肺 AVM 存在之间发现了遗传关联[相对风险=1.3（1.0018-1.7424)]。rs10987746-C 风险等位基因与一组人类淋巴母细胞系中 ENG RNA 表达降低相关（P=0.004）。此外，在血管生成活跃的人类肺腺癌组织中，但在未受累的静止肺中，rs10987746-C 与另一个 HHT 修饰因子 PTPN14 的表达相关（P=0.004）。在一组 69 只遗传异质种间近交系小鼠的正常肺组织中进行的定量 TAQMAN 表达分析表明，Eng、Acvrl1 和 Ptpn14 的表达水平之间存在强烈相关性（r2=0.75-0.9，P<1×10(-12)），进一步表明这三个基因在体内肺中的直接或间接相互作用。我们的数据表明，单个功能性 ENG 基因内的遗传变异影响 ENG 表达的定量和/或定性差异，从而导致 HHT1 中肺 AVM 的风险，并且为 PTPN14 参与体内 ENG/ALK1 肺生物学提供了相关性支持。已经表明 PTPN14 是 Yap/Taz 信号的负调节剂，该信号参与机械转导，为 ENG/ALK1 信号与机械应激之间提供了可能的分子联系。与肺 AVM 具有提示性遗传关联的 EMILIN2 也被报道在血管生成中与 Taz 相互作用。阐明调节内皮细胞中这些相互作用的分子机制最终可能为 HHT 治疗提供更合理的选择。
