基于计算机的 FANCA、FANCC 和 FANCG 基因突变的错义变异研究揭示了易导致范可尼贫血发病机制的高风险有害等位基因。

In silico study of missense variants of FANCA, FANCC and FANCG genes reveals high risk deleterious alleles predisposing to Fanconi anemia pathogenesis.

机构信息

Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia.

Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia.

出版信息

Gene. 2022 Feb 20;812:146104. doi: 10.1016/j.gene.2021.146104. Epub 2021 Dec 2.

DOI:10.1016/j.gene.2021.146104

PMID:34864095

Abstract

Among the 22 Fanconi anemia (FA) reported genes, 90% of mutational spectra were found in three genes, namely FANCA (64%), FANCC (12%) and FANCG (8%). Therefore, this study aimed to identify the high-risk deleterious variants in three selected genes (FANCA, FANCC, and FANCG) through various computational approaches. The missense variant datasets retrieved from the UCSC genome browser were analyzed for their pathogenicity, stability, and phylogenetic conservancy. A total of 23 alterations, of which 16 in FANCA, 6 in FANCC and one variant in FANCG, were found to be highly deleterious. The native and mutant structures were generated, which demonstrated a profound impact on the respective proteins. Besides, their pathway analysis predicted many other pathways in addition to the Fanconi anemia pathway, homologous recombination, and mismatch repair pathways. Hence, this is the first comprehensive study that can be useful for understanding the genetic signatures in the development of FA.

摘要

在已报道的 22 个范可尼贫血症（FA）基因中，90%的突变谱存在于三个基因中，即 FANCA（64%）、FANCC（12%）和 FANCG（8%）。因此，本研究旨在通过多种计算方法鉴定三个选定基因（FANCA、FANCC 和 FANCG）中的高风险有害变异。从 UCSC 基因组浏览器中检索到的错义变异数据集，分析其致病性、稳定性和种系保守性。共发现 23 种改变，其中 FANCA 中有 16 种，FANCC 中有 6 种，FANCG 中有 1 种变体被认为是高度有害的。生成了天然和突变体结构，这表明它们对各自的蛋白质有深远的影响。此外，它们的途径分析预测了除范可尼贫血途径、同源重组和错配修复途径之外的许多其他途径。因此，这是第一项全面的研究，可以帮助我们了解 FA 发展中的遗传特征。