Anti-ASAH1 monoclonal antibody, clone FQS23219

Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1(tmEx1) mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.

Objective: We identify chromosomal alterations, the methylation pattern and gene expression changes in pediatric ependymomas. Methods: CGH microarray, methylation and gene expression were performed through the Agilent platform. The results were analyzed with the software MatLab, MapViewer, DAVID, GeneCards and Hippie. Results: Amplification was found in 14q32.33, 2p22.3 and 8p22, and deletion was found in 8p11.23-p11.22 and 1q21.3. We observed 42.387 CpG islands with changes in their methylation pattern, in which we found 272 genes involved in signaling pathways related to carcinogenesis. We found 481 genes with altered expression. The genes IMMT,JHDMD1D, ASAH1, ZWINT, IPO7, GNAO1 and CISD3 were found to be altered among the three levels. Conclusion: The 2p22.3, 8p11.23-p11.22 and 14q32.33 regions were identified as the most important; the changes in the methylation pattern related to cell cycle and cancer genes occurred in MIB2, FGF18 and ITIH5. The IPO7, GNAO1 and ASAH1 genes may play a major role in ependymoma development. (C) 2016 Elsevier B.V. All rights reserved.