种系TP53 p.K164E乙酰化位点变异的临床和功能分析。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2024-01-10 Print Date: 2023-12-01 DOI:10.1101/mcs.a006290
Emilia Modolo Pinto, Enilze M S F Ribeiro, Jinling Wang, Aaron H Phillips, Richard W Kriwacki, Gerard P Zambetti
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引用次数: 0

摘要

TP53作为肿瘤抑制因子,通过控制细胞周期进程、DNA修复和细胞凋亡发挥关键作用。翻译后修饰,如DNA结合和c端调控域中特定赖氨酸残基的乙酰化,可调节其肿瘤抑制活性。在这项研究中,我们研究了在一位早发性乳腺癌患者中发现的种系TP53 p.K164E (NM_000546.5: c.490A>G)变异的功能后果,该患者有明显的癌症家族史。K164是位于p53 DNA结合域L2环的一个保守残基,翻译后被乙酰化修饰。在硅,体外和体内分析表明,谷氨酸替换在K164轻微破坏p53蛋白结构的稳定性,但显著损害序列特异性DNA结合,反激活和肿瘤细胞生长抑制。虽然p.K164E目前被不同的临床基因检测实验室认为是一种未知意义的变异,但本文提出的临床和实验室研究结果提供了强有力的证据,可以将TP53 p.K164E重新分类为一种可能的致病变异。
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Clinical and functional analysis of the germline TP53 p.K164E acetylation site variant.

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and carboxy-terminus regulatory domains modulate its tumor suppressor activities. In this study, we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early-onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes the p53 protein structure but significantly impairs sequence-specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and laboratory-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.

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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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