Mehdipour Parvin, Azarnezhad Asaad
Department of Medical genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran,
Department of Medical genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Front Biosci (Elite Ed). 2018 Mar 1;10(2):375-383. doi: 10.2741/e828.
The aim of this study was to trace D1853N in a proband affected with primary BC to explore the molecular, cellular and structural aspects of ATM. Exon 37 and splicing regions were PCR-sequenced. Allelic location of the alterations was determined by molecular cloning. Possible impact of alterations was investigated through the bioinformatics and protein expression assays. Five genetic variants including IVS 36-91 AA>TT, IVS 36-8 T>C, D1853N, IVS 37+47 A>G, IVS 37+60 Del T were found in the target regions of ATM and all the alterations were occurred heterezygously. IVS 36-8 T>C and D1853N were observed in blood and tumor tissue, whilst splicing variants were only occurred in tumor tissue. Missense D1853N alteration seems to be effective on 2D and 3D structure of ATM protein and the probability of splicing found to be decreased by intronic variants. Protein expression of ATM also confirmed the occurrence and functional impact of alterations. Results reflect a five-hit hypothesis in a proband with BC that influence ATM, as a guard of genomic stability, at molecular, cellular, and structural levels.
本研究的目的是在一名原发性乳腺癌患者中追踪D1853N，以探索ATM的分子、细胞和结构方面。对第37外显子和剪接区域进行PCR测序。通过分子克隆确定改变的等位基因位置。通过生物信息学和蛋白质表达分析研究改变的可能影响。在ATM的目标区域发现了5种基因变异，包括IVS 36-91 AA>TT、IVS 36-8 T>C、D1853N、IVS 37+47 A>G、IVS 37+60 Del T，所有改变均为杂合发生。在血液和肿瘤组织中观察到IVS 36-8 T>C和D1853N，而剪接变异仅发生在肿瘤组织中。错义D1853N改变似乎对ATM蛋白的二维和三维结构有影响，并且发现内含子变异会降低剪接的可能性。ATM的蛋白质表达也证实了改变的发生及其功能影响。结果反映了一名乳腺癌患者中影响ATM的五重打击假说，ATM作为基因组稳定性的守护者，在分子、细胞和结构水平上受到影响。
