在家族非骨髓性甲状腺癌中发现的CHEK2生殖系变异导致蛋白质结构和功能受损
Carolina Pires1, Inês J Marques1, Mariana Valério2
1Unidade de Investigação em Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal; NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
The Journal of biological chemistry
|February 17, 2024
概括
在家族非骨髓性甲状腺癌 (FNMTC) 家庭中发现了CHEK2基因的遗传变异. 这些CHEK2变种显示功能受损和聚合增加,表明在FNMTC发展中发挥了作用.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- 家族性非骨髓性甲状腺癌 (FNMTC) 占甲状腺癌的5-15%,但其遗传基础在很大程度上是未知的.
- 基因修复基因中的生殖系突变越来越多地与甲状腺癌 (TC) 的病因有关.
- 了解FNMTC遗传学对于改善诊断和临床管理至关重要.
研究的目的:
- 在两个受影响家庭中调查FNMTC的遗传基础.
- 在遗传性癌症倾向基因中识别和描述新的或已知的生殖系变异.
- 阐明已识别的变异对蛋白质结构和活性的功能影响.
主要方法:
- 94个遗传性癌症倾向基因的下一代测序.
- 在FNMTC家族中对已识别的变异进行分离分析.
- 生物物理特征,分子动力学模拟和CHEK2蛋白质变体的免疫组织化学.
主要成果:
- 两种生殖系CHEK2误解变异 (p.E321A和p.I157T) 在两种家族中被确定并与TC分离.
- 两种CHEK2变体都表现出结构稳定性受损,激酶活性受损,并且在体外增加了粉样纤维细胞形成的倾向.
- 与野生型相比,CHEK2变体在甲状腺瘤中表达水平更高.
结论:
- 鉴定到的CHEK2变种有助于FNMTC的遗传基础.
- 生物物理和in silico方法对于评估遗传变异的致病性非常有价值.
- 这些发现提供了关于CHEK2在甲状腺癌病理生理学和潜在的临床应用中的作用的见解.
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