Functional evaluation of a novel GLA causative mutation in Fabry disease
Functional evaluation of a novel GLA causative mutation in Fabry disease
复制标题
法布里病中新型 GLA 致病突变的功能评估
DOI：
10.1002/mgg3.864
复制
发表时间：
2019-07-18
影响因子：
2
通讯作者：
Wu, Changxin
中科院分区：
文献类型：
--
作者：
Li, Ping;Zhang, Lijuan;Wu, Changxin
法布里病（FD）是一种罕见的x -连锁α -半乳糖苷酶a （GLA）缺乏症，导致多种细胞类型中球三烷基神经酰胺的进行性溶酶体积累。由于分子诊断工具的进步，在FD中发现了越来越多的GLA致病突变。我们发现一个新的突变在一个中国家庭主要法布里病肾病。方法对GLA基因的所有编码区和外显子-内含子剪接区进行序列分析。我们通过GLA mRNA分析、序列分析和同源性建模、定点诱变和体外表达研究来评估其对GLA蛋白的影响。结果我们发现了一个新的杂合错义突变C . 280t >c在我们的患者肾脏受累的可变表型表现。在GFP-GLA-MT转染的HEK293T细胞中，新的GLA变体导致GLA mrna的低表达，野生型GLA的二硫酸盐桥结构受损或丧失，GLA活性降低和核形状缺陷。结论一种新的GLA错义突变C . 280t >c （Cys94Arg）在中国一个以FD肾脏表现为主的家族中被发现。本研究揭示了C . 280t >C突变致FD的发病机制，为FD的准确诊断和精准医疗干预提供科学依据。
Background Fabry disease (FD), a rare X-linked alpha-galactosidase A (GLA) deficiency, resulting in progressive lysosomal accumulation of globotriaosylceramide in a variety of cell types. More and more disease-causing mutations in GLA have been identified in FD due to the advancement of molecular diagnostic tools. We found a novel mutation in a Chinese family with predominant Fabry's disease nephropathy. Methods All coding regions and exon-intron splice junctions of the GLA gene were sequenced to find sequence variations. We evaluated the impact on the GLA protein by analysis of the GLA mRNA, by sequential analysis and homology modeling, and by site-directed mutagenesis and in vitro expression studies. Results We identified a novel heterozygous missense mutation c.280T>C in our patient with variable phenotypic presentations of renal involvement. The novel GLA variant results in low expression of GLA mRNAs, impaired or loss of the disulfate bridge structure of wild-type GLA, reduced GLA activity and defected nuclear shape in the GFP-GLA-MT transfected HEK293T cells. Conclusion A novel GLA missense mutation, c.280T>C (Cys94Arg), was found in a Chinese family with predominant renal manifestations of FD. Our study reveals the pathogenesis of c.280T>C mutation to FD and provides scientific foundation for accurate diagnosis and precise medical intervention for FD.