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other·preclinical research, neurology, biomedical research, pediatrics·PMC10275725

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

Human Genetics and Genomics Advances · 9 authors, 8 centres

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TL;DR

The study used patient-derived cells and a mouse model to show that DHPS mutations reduce the enzyme's activity, leading to a shift in eIF5A modifications that impairs mRNA translation and disrupts neuronal development.

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Using patient-derived lymphoblast cell lines and a mouse model with brain-specific Dhps deletion, the authors demonstrated that human DHPS variants cause reduced DHPS protein abundance and impaired enzyme activity. This leads to a shift in eukaryotic initiation factor 5A (eIF5A) modifications, increasing the nuclear acetylated form (eIF5A^AcK47^) and decreasing the cytoplasmic hypusinated form (eIF5A^HYP^). The resulting defect in mRNA translation altered the synthesis of proteins critical for neuronal development and function. Limitations include the use of a brain-specific knockout model that may not fully recapitulate all human clinical features, and the study's primary focus on molecular mechanisms rather than direct clinical outcomes.

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other

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preclinical research

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ORIGINAL PAPER

PMC10275725

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

Human Genetics and Genomics Advances

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ABSTRACT

Summary 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.

CITATION EXPORT

Leah R. Padgett, Mollie R. Shinkle, Spencer Rosario et al.. Deoxyhypusine synthase mutations alter the post-translational modification of eukaryotic initiation factor 5A resulting in impaired human and mouse neural homeostasis. Human Genetics and Genomics Advances. (2023). https://doi.org/10.1016/j.xhgg.2023.100206

AUTHORS

9 · 8 CENTRES

Leah R. Padgett, Mollie R. Shinkle, Spencer Rosario, Tracy Murray Stewart, Jackson R. Foley, Robert A. Casero, Myung Hee Park, Wendy K. Chung, Teresa L. Mastracci

1Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA
2Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA
3Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA
4Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
5National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA
6Departments of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA
7Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
8Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA