来自用户 惊鸿 的文献。
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惊鸿
(2022-08-14 18:12):
#paper doi:10.1101/2022.08.08.503198 Bilallelic germline mutations in MAD1L1 induce a novel syndrome of aneuploidy with high tumor susceptibility
MAD1L1是编码纺锤体组装检查点 (SAC) 蛋白MAD1的基因,发生在一名36岁的患有十几个肿瘤的女性身上,包括五个恶性肿瘤。外周血细胞的功能研究表明缺乏全长蛋白质和SAC反应不足,导致细胞遗传学和单细胞 (sc) 检测到约30-40% 的非整倍体细胞DNA分析。对患者血细胞的scRNA-seq分析确定了线粒体应激伴随全身炎症,干扰素和NFkB信号增强。MAD1L1突变还导致 γ δ T细胞的特异性克隆扩增,增加了18号染色体并增强了细胞毒性,以及具有慢性淋巴细胞白血病细胞特征的染色体12增益和转录组特征的中间b细胞。这些数据表明MAD1L1突变是一种新的具有全身炎症和前所未有的肿瘤易感性的非整倍体综合征的原因。
仅仅一个基因片段就可以给全身带来变化,这些变化有好有坏,所以基因编辑不是消消乐,是一个严谨的技术,这是一个基因工程师应有的心态
bioRxiv,
2022.
DOI: 10.1101/2022.08.08.503198
Abstract:
Aneuploidy is a frequent feature of human tumors. Germline mutations leading to aneuploidy are very rare in humans, and their tumor-promoting properties are mostly unknown at the molecular level. We …
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Aneuploidy is a frequent feature of human tumors. Germline mutations leading to aneuploidy are very rare in humans, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, the gene encoding the Spindle Assembly Checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias, including five malignant tumors. Functional studies in peripheral blood cells demonstrated lack of full-length protein and deficient SAC response, resulting in ∼30-40% of aneuploid cells as detected by cytogenetic and single-cell (sc) DNA analysis. scRNA-seq analysis of patient blood cells identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFkB signaling. The inference of chromosomal aberrations from scRNA-seq analysis detected inflammatory signals both in aneuploid and euploid cells, suggesting a non-cell autonomous response to aneuploidy. In addition to random aneuploidies, MAD1L1 mutations resulted in specific clonal expansions of γδ T-cells with chromosome 18 gains and enhanced cytotoxic profile, as well as intermediate B-cells with chromosome 12 gains and transcriptomic signatures characteristic of chronic lymphocytic leukemia cells. These data point to MAD1L1 mutations as the cause of a new aneuploidy syndrome with systemic inflammation and unprecedented tumor susceptibility.
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