GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.

IF 8.1 1区 生物学 Q1 GENETICS & HEREDITY American journal of human genetics Pub Date : 2024-07-11 Epub Date: 2024-06-24 DOI:10.1016/j.ajhg.2024.05.020
Jian Ren, Ziwei Cui, Chendan Jiang, Leiming Wang, Yunqian Guan, Yeqing Ren, Shikun Zhang, Tianqi Tu, Jiaxing Yu, Ye Li, Wanru Duan, Jian Guan, Kai Wang, Hongdian Zhang, Dong Xing, Mark L Kahn, Hongqi Zhang, Tao Hong
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Abstract

Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.

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GNA14 和 GNAQ 体细胞突变会导致脊柱和颅内轴外海绵状血管瘤。
轴外海绵状血管瘤(ECH)是一种复杂的血管病变,主要发生在脊柱和海绵窦。由于其血管性和弥漫性,切除它们会带来很大的风险,而且人们对其遗传基础的了解仍不全面。我们的方法包括采用全外显子组测序和靶向深度测序对 31 个 ECHs 组织样本进行基因分析。我们在体外和体内探索了这些突变诱导的下游信号通路、基因表达变化以及由此导致的表型转变。在我们的队列中,77.4%的样本存在GNA14、GNAQ或GJA4的体细胞错义变异。转录组分析强调了明显的通路上调,GNAQ c.626A>G(p.Gln209Arg)突变升高了PI3K-AKT-mTOR和血管生成相关通路,而GNA14 c.614A>T(p.Gln205Leu)突变导致MAPK和血管生成相关通路上调。通过小鼠异种移植模型,我们观察到这些突变导致血管扩大。此外,我们还对一名携带 GNAQ c.626A>G (p.Gln209Arg) 变异的 14 岁患者进行了雷帕霉素治疗,结果皮肤海绵状血管瘤逐渐消退,运动能力得到改善,而且副作用极小。了解这些突变及其途径为开发治疗对现有疗法产生抗药性的 ECHs 的疗法奠定了基础。事实上,在这项研究中,雷帕霉素的应用凸显了靶向治疗在治疗这些复杂病变方面的前景。
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来源期刊
CiteScore
14.70
自引率
4.10%
发文量
185
审稿时长
1 months
期刊介绍: The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.
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