Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis.

Autor:	Padgett LR; Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA., Shinkle MR; Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA., Rosario S; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA., Stewart TM; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Foley JR; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Casero RA Jr; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Park MH; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA., Chung WK; Departments of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA., Mastracci TL; Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jazyk:	angličtina
Zdroj:	HGG advances [HGG Adv] 2023 May 18; Vol. 4 (3), pp. 100206. Date of Electronic Publication: 2023 May 18 (Print Publication: 2023).
DOI:	10.1016/j.xhgg.2023.100206
Abstrakt:	DHPS deficiency is a rare genetic disease caused by biallelic hypomorphic variants in the Deoxyhypusine synthase ( DHPS ) gene. The DHPS enzyme functions in mRNA translation by catalyzing the post-translational modification, and therefore activation, of eukaryotic initiation factor 5A (eIF5A). The observed clinical outcomes associated with human mutations in DHPS include developmental delay, intellectual disability, and seizures. Therefore, to increase our understanding of this rare disease, it is critical to determine the mechanisms by which mutations in DHPS alter neurodevelopment. In this study, we have generated patient-derived lymphoblast cell lines and demonstrated that human DHPS variants alter DHPS protein abundance and impair enzyme function. Moreover, we observe a shift in the abundance of the post-translationally modified forms of eIF5A; specifically, an increase in the nuclear localized acetylated form (eIF5A AcK47 ) and concomitant decrease in the cytoplasmic localized hypusinated form (eIF5A HYP ). Generation and characterization of a mouse model with a genetic deletion of Dhps in the brain at birth shows that loss of hypusine biosynthesis impacts neuronal function due to impaired eIF5A HYP -dependent mRNA translation; this translation defect results in altered expression of proteins required for proper neuronal development and function. This study reveals new insight into the biological consequences and molecular impact of human DHPS deficiency and provides valuable information toward the goal of developing treatment strategies for this rare disease. Competing Interests: W.K.C. is on the Board of Directors for Prime Medicine and on the Scientific Advisory Board for the Regeneron Genetics Center. (© 2023 The Authors.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu