A novel somatic mutation in GNB2 provides new insights to the pathogenesis of Sturge-Weber syndrome.
A novel somatic mutation in GNB2 provides new insights to the pathogenesis of Sturge-Weber syndrome.
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DOI：
10.1093/hmg/ddab144
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发表时间：
2021-10-13
影响因子：
3.5
通讯作者：
Selmer KK
中科院分区：
文献类型：
--
作者：
Fjær R;Marciniak K;Sundnes O;Hjorthaug H;Sheng Y;Hammarström C;Sitek JC;Vigeland MD;Backe PH;Øye AM;Fosse JH;Stav-Noraas TE;Uchiyama Y;Matsumoto N;Comi A;Pevsner J;Haraldsen G;Selmer KK
斯特奇-韦伯综合征 (SWS) 是一种神经皮肤疾病，其特征是影响皮肤、眼睛和大脑软脑膜的血管畸形，可导致青光眼、癫痫发作和智力障碍。 GNAQ 基因（编码异三聚体 G 蛋白的 α 链）中发现了一种导致疾病的体细胞错义突变，这引发了了解 G 蛋白如何促进 SWS 发病机制的努力。该突变主要在内皮细胞中检测到，目前被认为会影响下游 MAPK 信号传导。在这项针对 6 名患有经典 SWS 的挪威患者的研究中，我们旨在通过对皮肤活检中的 DNA 进行深度测序来识别体细胞突变。令人惊讶的是，一名患者的 GNAQ 突变呈阴性，但却携带 GNB2 体细胞突变 (NM_005273.3:c.232A>G, p.Lys78Glu)，该突变编码相同 G 蛋白复合物的 β 链。 G 蛋白中突变氨基酸的位置对于复杂的重新组装至关重要。因此，重组和连续信号传导失败可能是这两种突变的结果。内皮细胞中突变蛋白的异位表达表明，任一突变体的表达都会减少细胞增殖，但对 MAPK 信号传导的调节不同，这表明 MAPK 信号传导失调不能完全解释 SWS 表型。相反，两种突变体都减少了 Yes 相关蛋白 (YAP) 的合成，YAP 是 Hippo 信号通路的转录共激活因子，表明该通路在 SWS 的血管发病机制中发挥着关键作用。 GNB2 突变的发现为 SWS 的发病机制提供了新的线索，并表明未来治疗靶点的研究应针对 YAP，而不是 MAPK 信号通路。
Sturge–Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations affecting skin, eyes and leptomeninges of the brain, which can lead to glaucoma, seizures and intellectual disability. The discovery of a disease-causing somatic missense mutation in the GNAQ gene, encoding an alpha chain of heterotrimeric G-proteins, has initiated efforts to understand how G-proteins contribute to SWS pathogenesis. The mutation is predominantly detected in endothelial cells and is currently believed to affect downstream MAPK signalling. In this study of six Norwegian patients with classical SWS, we aimed to identify somatic mutations through deep sequencing of DNA from skin biopsies. Surprisingly, one patient was negative for the GNAQ mutation, but instead harbored a somatic mutation in GNB2 (NM_005273.3:c.232A>G, p.Lys78Glu), which encodes a beta chain of the same G-protein complex. The positions of the mutant amino acids in the G-protein are essential for complex reassembly. Therefore, failure of reassembly and continuous signalling is a likely consequence of both mutations. Ectopic expression of mutant proteins in endothelial cells revealed that expression of either mutant reduced cellular proliferation, yet regulated MAPK signalling differently, suggesting that dysregulated MAPK signalling cannot fully explain the SWS phenotype. Instead, both mutants reduced synthesis of Yes-associated protein (YAP), a transcriptional co-activator of the Hippo signalling pathway, suggesting a key role for this pathway in the vascular pathogenesis of SWS. The discovery of the GNB2 mutation sheds novel light on the pathogenesis of SWS and suggests that future research on targets of treatment should be directed towards the YAP, rather than the MAPK, signalling pathway.
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影响因子：
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