Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting a systemic vascular phenotype, vascular malformations occur as focal lesions in discrete anatomic locations. The inconsistency between genotype and phenotype has provoked debate over whether haploinsufficiency or a different mechanism gives rise to the vascular malformations. We previously showed that HHT-associated skin telangiectases develop by a two-hit mutation mechanism in an HHT gene. However, somatic mutations were identified in only half of the telangiectases, raising the question whether a second-hit somatic mutation is a necessary (required) event in HHT pathogenesis. Here, we show that another mechanism for the second hit is loss of heterozygosity across the chromosome bearing the germline mutation. Secondly, we investigate the two-hit mutation mechanism for internal organ AVMs, the source of much of the morbidity of HHT. Here, we identified somatic molecular genetic events in eight liver telangiectases, including point mutations and a loss of heterozygosity event. We also identified somatic mutations in one pulmonary AVM and two brain AVMs, confirming that mucocutaneous and internal organ vascular malformations undergo the same molecular mechanisms. Together, these data argue that bi-allelic loss of function in an HHT gene is a required event in the pathogenesis of HHT-associated vascular malformations.

中文翻译：

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遗传性出血性毛细血管扩张症动静脉畸形的体细胞突变支持双等位基因 two-hit 突变的发病机制


遗传性出血性毛细血管扩张症 （HHT） 是一种遗传性血管畸形疾病，其特征是内脏器官皮肤粘膜毛细血管扩张和动静脉畸形 （AVM）。HHT 是由 3 个基因之一的功能丧失突变遗传引起的。尽管 HHT 个体在整个身体中对这些基因之一的单倍体不足，而不是表现出全身血管表型，但血管畸形在离散的解剖位置以局灶性病变的形式发生。基因型和表型之间的不一致引发了关于是单倍体不足还是不同机制导致血管畸形的争论。我们之前表明，HHT 相关的皮肤毛细血管扩张酶是通过 HHT 基因中的两次命中突变机制发展而来的。然而，仅在一半的毛细血管扩张酶中鉴定出体细胞突变，这提出了一个问题，即二次打击的体细胞突变是否是 HHT 发病机制中的必要 （required） 事件。在这里，我们表明第二次命中的另一种机制是带有种系突变的染色体上的杂合性丢失。其次，我们研究了内脏器官 AVM 的 two-hit 突变机制，这是 HHT 大部分发病率的来源。在这里，我们在 8 个肝脏毛细血管扩张酶中鉴定了体细胞分子遗传事件，包括点突变和杂合性事件丢失。我们还在 1 个肺 AVM 和 2 个脑 AVM 中发现了体细胞突变，证实了皮肤粘膜和内脏器官血管畸形经历相同的分子机制。总之，这些数据表明 HHT 基因中的双等位基因功能丧失是 HHT 相关血管畸形发病机制中的必要事件。