Large MAF家族的致病突變預測方法

Abstract

Large MAF家族，其成員包括MAFA，MFAB，c-MAF和NRL，在細胞分化和細胞類型鑑定中扮演非常重要的腳色。此家族的特徵為皆含有亮氨酸拉鍊（bZIP）的轉錄因子。過去的臨床研究報告了人類Large MAF基因的點突變與遺傳性疾病的高度相關性，惟其中MAFA中的突變和臨床相關性尚未徹底被研究。由於MAF蛋白中的結構域有高度相似性，基於MAF家族其他成員大部分已有相當程度的發現，因此本研究的目標在根據其家族其他成員的臨床研究結果及成員間的高度相似性，來辨認MAFA中的新致病突變。為了辨識突變位置，首先從OMIM和ClinVar等資料庫中審查其他Large MAF基因中的所有疾病相關點突變；接下來，通過比對軟件ClustalX和Jalview分析從線上數據庫UniProt所獲得的MAF氨基酸序列。結果顯示，點突變的可能位置大部分位於反式激活域中。進一步將點突變的可能位置與健康人群中存在的疾病特異性點突變比較，及使用REVEL分析罕見錯義變體的可能性。綜上所述，本研究之結果為辨識Large MAF家族致病點突變位置提供了一種新的篩選方法，期望該方法未來可用於精準醫療。

The large MAF family, including MAFA, MFAB, c-MAF and NRL, is known as a group of leucine zipper-containing transcription factors in the AP1 superfamily that plays important roles in cellular differentiation and cell type identification. Previous clinical studies reported the correlations between hereditary diseases and point mutations within human large MAF genes, whereas the mutations in MAFA and the clinical relevant have not been studied thoroughly. Since the domains in MAF proteins are highly conserved and contain pathogenic mutations, this study aimed to discover and identify the novel pathogenic mutations in MAFA. To identify mutation locations, all disease-related point mutations in other large MAF genes were firstly reviewed from the curated database such as OMIM and ClinVar. Next, amino acid sequences of MAFs obtained from online database UniProt were analyzed by alignment software, ClustalX and Jalview. The result demonstrated that the potential candidate mutations locate in transactivation domain included phosphorylation sites. The candidate mutations were further aligned with the disease-specific point mutations existed in healthy population and analyzed the possibility of rare missense variants using REVEL. In summary, these findings provided a novel screening method to identify pathogenic mutation points of large MAF family and this method could be applicable for the precision medicine.