Multi-omics approach reveals genes and pathways affected in Miller-Dieker Syndrome
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PROVIDER: PRJNA1039294 | ENA |
REPOSITORIES: ENA
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Project description:Miller-Dieker Syndrome (MDS) is a rare neurogenetic condition resulting from a heterozygous deletion of 26 genes in the MDS locus on human chromosome 17. Often MDS patients die in utero but of those who are born, only ~10% reach ten years old. Current treatments for MDS are based on the individual’s symptoms, which aim to prevent complications and control seizures. A detailed understanding of the pathogenesis of MDS through gene expression studies would be useful in developing precise medical approaches toward MDS. To better understand MDS at the molecular level, we performed RNA sequencing on RNA and mass spectrometry on total protein isolated from BJ (non-MDS) cells and GM06097 (MDS) cells, which were derived from a healthy and an MDS patient, respectively. Differentially expressed genes (DEGs) at the RNA and protein levels involved genes associated with phenotypic features reported in MDS patients (CACNG4, ADD2, NEAS, SHANK2), signaling pathways (WNT, GABBR2, CAMK2B, TRAM-1), and nervous system development (CAMK2B, BEX1, AHNAK). Phenotypic assays validated enhanced calcium signaling, cell migration defects and downregulated protein translation in MDS. Interestingly, methyltransferase-like protein 16 (METTL16), a protein encoded in the MDS locus, displayed a significant role in cell migration and protein translation defects in MDS cells. Although DNA and RNA modifying enzymes were among the DEGs and the intracellular SAM/SAH ratio was 8-fold lower in MDS cells, global nucleoside modifications remained unchanged. Thus, this study identified specific genes and pathways responsible for the gene expression changes, which could lead to better therapeutics for MDS patients.
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