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从潜在的林奇综合征患者中对MMR基因VUS进行功能分析

Marwa Mahdouani^1,2, Drenushe Zhuri³, Hazal Sezginer Guler³

¹Laboratory of Cytogenetics, Molecular Genetics and Human Reproduction Biology, Farhat Hached University Hospital, Sousse, Tunisia.

|June 6, 2024

概括

在DNA不匹配修复基因中的失活变体导致林奇综合征. 这项研究发现,两种MLH1删除变异极大地破坏了MLH1蛋白的稳定,导致不匹配修复缺陷,有助于临床管理.

科学领域:

遗传学和分子生物学
在瘤学瘤学.
生物化学生化学

背景情况:

林奇综合征是一种遗传性癌症倾向,由DNA不匹配修复 (MMR) 基因 (MLH1,MSH2,MSH6,PMS2) 的失活变体引起.
在MMR基因中,某些小编码变异的功能影响,包括误解和框架内删除,仍然不确定,使临床解释复杂化.
这些变异的准确分类对于遗传咨询和林奇综合征家族的临床管理至关重要.

研究的目的:

研究在土耳其和突尼斯的结直肠癌患者中发现的MLH1和MSH2变异的功能后果.
为了确定特定的误解和框架内删除变异是否会损害MLH1蛋白稳定性或MMR活性.
为了改善变异分类,将体外功能数据与in silico预测和临床观察相关联.

主要方法:

对变种携带者进行临床数据收集和家族史分析.
生物化学实验室测试以评估特定变异的MLH1蛋白稳定性和MMR活性.
在分析包括结构预测和研究变体的保护评估.

主要成果:

两种框架转移变异 (MLH1 p.(His727Profs*57) 和MSH2 p.(Thr788Asnfs*11) 被归类为致病性.
误解变体 (MLH1 p.(Asn338Ser) 和p.(Gly181Ser)) 没有影响蛋白质功能.
在MLH1中,有两种框架内删除变异 (p.(Val647-Leu650del) 和p.(Lys678_Cys680del)) 导致显著的蛋白质不稳定性和MMR缺乏,与结构分析一致.

结论:

在MLH1中的框架内删除可以通过破坏MLH1蛋白的稳定和损害MMR功能的方式引起林奇综合征.
功能和结构分析为生物化学测试结果提供了分子解释,增强了变体解释.
将功能数据与临床信息相结合,提高了基因测试的证据价值,促进了对林奇综合征家族的更好管理.

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