Datamining approaches for examining the low prevalence of N-acetylglutamate synthase deficiency and understanding transcriptional regulation of urea cycle genes

Ljubica Caldovic, Center for Genetic Medicine Research, Children's National Research Institute, Children's National Hospital, Washington, DC, USA.
Julie J. Ahn, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Jacklyn Andricovic, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Veronica M. Balick, Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Mallory Brayer, Department of Biological Sciences, The George Washington University, Washington, DC, USA.
Pamela A. Chansky, The Institute for Biomedical Science, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Tyson Dawson, The Institute for Biomedical Science, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Alex C. Edwards, The Institute for Biomedical Science, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Sara E. Felsen, The Institute for Biomedical Science, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Karim Ismat, Center for Genetic Medicine Research, Children's National Research Institute, Children's National Hospital, Washington, DC, USA.
Sveta V. Jagannathan, The Institute for Biomedical Science, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Brendan T. Mann, Department of Microbiology, Immunology, and Tropical Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Jacob A. Medina, The Institute for Biomedical Science, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Toshio Morizono, College of Science and Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
Michio Morizono, College of Science and Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
Shatha Salameh, Department of Pharmacology & Physiology, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.
Neerja Vashist, Center for Genetic Medicine Research, Children's National Research Institute, Children's National Hospital, Washington, DC, USA.
Emily C. Williams, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Zhe Zhou, Department of Civil and Environmental Engineering, The George Washington University, Washington, DC, USA.
Hiroki Morizono, Center for Genetic Medicine Research, Children's National Research Institute, Children's National Hospital, Washington, DC, USA.

Document Type

Journal Article

Publication Date

10-17-2023

Journal

Journal of inherited metabolic disease

DOI

10.1002/jimd.12687

Keywords

AMPK; NAGS; NAGS deficiency; nitrogen load; transcriptional regulation; urea cycle

Abstract

Ammonia, which is toxic to the brain, is converted into non-toxic urea, through a pathway of six enzymatically catalyzed steps known as the urea cycle. In this pathway, N-acetylglutamate synthase (NAGS, EC 2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme A. NAGS deficiency (NAGSD) is the rarest of the urea cycle disorders, yet is unique in that ureagenesis can be restored with the drug N-carbamylglutamate (NCG). We investigated whether the rarity of NAGSD could be due to low sequence variation in the NAGS genomic region, high NAGS tolerance for amino acid replacements, and alternative sources of NAG and NCG in the body. We also evaluated whether the small genomic footprint of the NAGS catalytic domain might play a role. The small number of patients diagnosed with NAGSD could result from the absence of specific disease biomarkers and/or short NAGS catalytic domain. We screened for sequence variants in NAGS regulatory regions in patients suspected of having NAGSD and found a novel NAGS regulatory element in the first intron of the NAGS gene. We applied the same datamining approach to identify regulatory elements in the remaining urea cycle genes. In addition to the known promoters and enhancers of each gene, we identified several novel regulatory elements in their upstream regions and first introns. The identification of cis-regulatory elements of urea cycle genes and their associated transcription factors holds promise for uncovering shared mechanisms governing urea cycle gene expression and potentially leading to new treatments for urea cycle disorders.

Department

Genomics and Precision Medicine

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