Gaucher Disease: Transcriptome Analyses Using Microarray or mRNA Sequencing in a Gba1 Mutant Mouse Model Treated with Velaglucerase alfa or ImigluceraseReportar como inadecuado




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Gaucher disease type 1, an inherited lysosomal storage disorder, is caused by mutations in GBA1 leading to defective glucocerebrosidase GCase function and consequent excess accumulation of glucosylceramide-glucosylsphingosine in visceral organs. Enzyme replacement therapy ERT with the biosimilars, imiglucerase imig or velaglucerase alfa vela improves-reverses the visceral disease. Comparative transcriptomic effects microarray and mRNA-Seq of no ERT and ERT imig or vela were done with liver, lung, and spleen from mice having Gba1 mutant alleles, termed D409V-null. Disease-related molecular effects, dynamic ranges, and sensitivities were compared between mRNA-Seq and microarrays and their respective analytic tools, i.e. Mixed Model ANOVA microarray, and DESeq and edgeR mRNA-Seq. While similar gene expression patterns were observed with both platforms, mRNA-Seq identified more differentially expressed genes DEGs ∼3-fold than the microarrays. Among the three analytic tools, DESeq identified the maximum number of DEGs for all tissues and treatments. DESeq and edgeR comparisons revealed differences in DEGs identified. In 9V-null liver, spleen and lung, post-therapy transcriptomes approximated WT, were partially reverted, and had little change, respectively, and were concordant with the corresponding histological and biochemical findings. DEG overlaps were only 8–20% between mRNA-Seq and microarray, but the biological pathways were similar. Cell growth and proliferation, cell cycle, heme metabolism, and mitochondrial dysfunction were most altered with the Gaucher disease process. Imig and vela differentially affected specific disease pathways. Differential molecular responses were observed in direct transcriptome comparisons from imig- and vela-treated tissues. These results provide cross-validation for the mRNA-Seq and microarray platforms, and show differences between the molecular effects of two highly structurally similar ERT biopharmaceuticals.



Autor: Nupur Dasgupta , You-Hai Xu , Sunghee Oh, Ying Sun, Li Jia, Mehdi Keddache, Gregory A Grabowski

Fuente: http://plos.srce.hr/



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