DeBose-Scarlett Evon, Marchuk Douglas A
Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
J Clin Med. 2025 Jun 24;14(13):4479. doi: 10.3390/jcm14134479.
Historically, the factor(s) that stimulate vascular malformation genesis in hereditary hemorrhagic telangiectasia (HHT) has been hotly debated. Once heterozygous loss-of-function germline mutations in , , or were discovered in individuals with HHT, haploinsufficiency, a 50% reduction in the encoded protein, was proposed as the molecular mechanism of HHT. However, the focal and discrete nature of HHT-associated vascular malformations suggested to others that vascular malformation genesis requires an additional, local trigger. In this review, we discuss the evidence for the Knudsonian two-hit mutation mechanism of vascular malformation pathogenesis in HHT, where the inherited, heterozygous mutation is augmented by an acquired somatic mutation in the remaining normal copy of the gene. We consider the mechanisms of HHT-vascular malformation development in the broader context of the emerging role of somatic mutations in both sporadic and inherited vascular malformations. We discuss different mechanisms of biallelic gene inactivation in HHT, difficulties with the detection of all possible mechanisms of biallelic inactivation, and issues related to the somatic mosaic nature of the lesion. We then discuss the critical importance of non-genetic factors on the pathogenesis of HHT-associated vascular malformations. Finally, we discuss the implications of the two-hit mutation mechanism for the design of novel treatments for HHT.
从历史角度来看，遗传性出血性毛细血管扩张症（HHT）中刺激血管畸形发生的因素一直备受争议。一旦在HHT患者中发现、或的杂合性功能丧失种系突变，单倍剂量不足（即编码蛋白减少50%）就被提出作为HHT的分子机制。然而，HHT相关血管畸形的局灶性和离散性让其他人认为血管畸形的发生需要额外的局部触发因素。在这篇综述中，我们讨论了HHT中血管畸形发病机制的Knudson二次打击突变机制的证据，即在遗传性杂合突变的基础上，基因的剩余正常拷贝发生获得性体细胞突变。我们在体细胞突变在散发性和遗传性血管畸形中日益重要的更广泛背景下，考虑HHT血管畸形发展的机制。我们讨论了HHT中双等位基因失活的不同机制、检测所有可能的双等位基因失活机制的困难以及与病变体细胞镶嵌性质相关的问题。然后我们讨论非遗传因素对HHT相关血管畸形发病机制的关键重要性。最后，我们讨论二次打击突变机制对HHT新型治疗设计的影响。
