Submission
| Title: | Multi-omics approach to study novel genes and pathways affected in Miller-Dieker Syndrome |
| Presenter: | Gowthami Mahendran |
| Institution: | University of Notre Dame |
| Authors: | Gowthami Mahendran, Kurtis Breger, Philip J. McCown, Jacob P. Hulewicz, Jessica A. Brown University of Notre Dame |
Abstract
| Background/Significance/Rationale: | Miller-Dieker Syndrome (MDS) is a neurogenetic condition resulting from a heterozygous deletion of MDS locus genes. Often MDS patients die in utero, but children who are born display lissencephaly, neurological disorders, epilepsy etc. Generally, the life expectancy is related to the severity of the lissencephaly. Hence, understanding the MDS pathogenesis linked to various pathways could be useful in therapeutics. |
| Methods: | To better understand MDS at the molecular level, we utilized BJ (healthy) and GM06097 (MDS patient) cells. RNA-seq (transcriptomics) and tandem mass spectrometry (proteomics) were performed to analyze gene expression alterations in MDS. |
| Results/Findings: | At the RNA level, significant up (1286) and downregulated (1515) genes in GM06097 cells were analyzed using Ingenuity Pathway Analysis (IPA), which suggested suppressed synaptogenesis and enhanced cardiac hypertrophy. At the protein level, significant up (213) and downregulated (237) genes in GM06097 cells have roles in synaptogenesis, skeletal system, and organ development. Among the differentially expressed RNAs and proteins, several genes (mettl16, camk2b, bex1, nrxn3, gabbr2, stx1a) are linked to nervous system development and phenotypic features reported in MDS patients. Specifically, mettl16 (methyltransferase like protein-16) is a gene located within the MDS locus that functions as an m6A writer protein. It showed reduced RNA and protein level expression at ~50% in MDS cells. Western blots validated significantly altered proteins in our proteomics results. |
| Conclusions/Discussion: | Our multi-omics study proposes a significant overlap between the altered pathways identified in MDS and other metabolic and cellular pathways at the RNA and protein levels with associated genes and proteins. This observation implied that MDS patients have higher susceptibility to cancer and different organismal injuries. |
| Translational/Human Health Impact: | Hence, our study will pave the way for understanding the implication of genes related to MDS, to help identify therapeutic biomarkers against MDS. |
