Multi-Omics Approach Reveals Genes and Pathways Affected in Miller-Dieker Syndrome.

Autor: Mahendran G; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA., Breger K; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA., McCown PJ; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.; Department of Internal Medicine, Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, MI, 48109, USA., Hulewicz JP; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA., Bhandari T; Department of Chemistry, University of Cincinnati, Cincinnati, OH, 45221, USA., Addepalli B; Department of Chemistry, University of Cincinnati, Cincinnati, OH, 45221, USA., Brown JA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA. jbrown33@nd.edu.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2024 Nov 07. Date of Electronic Publication: 2024 Nov 07.
DOI: 10.1007/s12035-024-04532-7
Abstrakt: Miller-Dieker syndrome (MDS) is a rare neurogenetic disorder resulting from a heterozygous deletion of 26 genes in the MDS locus on human chromosome 17. MDS patients often die in utero and only 10% of those who are born reach 10 years of age. Current treatments mostly 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 individual 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, SPTAN1, SHANK2), signaling pathways (GABBR2, CAMK2B, TRAM-1), and nervous system development (CAMK2B, BEX1, ARSA). Functional assays validated enhanced calcium signaling, downregulated protein translation, and cell migration defects in MDS. Interestingly, overexpression of methyltransferase-like protein 16 (METTL16), a protein encoded in the MDS locus, restored defects in protein translation, phosphor states of mTOR (mammalian target of rapamycin) pathway regulators, and cell migration in MDS cells. Although DNA- and RNA-modifying enzymes were among the DEGs and the intracellular SAM/SAH ratio was eightfold 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.
Competing Interests: Declarations. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Conflict of Interest: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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