Noncoding sequence variants define a novel regulatory element in the first intron of the N-acetylglutamate synthase gene

J. Haberle, M.B. Moore, N. Haskins, V. Rufenacht, D. Rokicki, E. Rubio-Gozalbo, M. Tuchman, N. Longo, M. Yandell, A. Andrews, N. AhMew, L. Caldovic*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

N-acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder caused either by decreased expression of the NAGS gene or defective NAGS enzyme resulting in decreased production of N-acetylglutamate (NAG), an allosteric activator of carbamylphosphate synthetase 1 (CPS1). NAGSD is the only urea cycle disorder that can be effectively treated with a single drug, N-carbamylglutamate (NCG), a stable NAG analog, which activates CPS1 to restore ureagenesis. We describe three patients with NAGSD due to four novel noncoding sequence variants in the NAGS regulatory regions. All three patients had hyperammonemia that resolved upon treatment with NCG. Sequence variants NM_153006.2:c.427-222G>A and NM_153006.2:c.427-218A>C reside in the 547 bp-long first intron of NAGS and define a novel NAGS regulatory element that binds retinoic X receptor alpha. Sequence variants NC_000017.10:g.42078967A>T (NM_153006.2:c.-3065A>T) and NC_000017.10:g.42078934C>T (NM_153006.2:c.-3098C>T) reside in the NAGS enhancer, within known HNF1 and predicted glucocorticoid receptor binding sites, respectively. Reporter gene assays in HepG2 and HuH-7 cells demonstrated that all four substitutions could result in reduced expression of NAGS. These findings show that analyzing noncoding regions of NAGS and other urea cycle genes can reveal molecular causes of disease and identify novel regulators of ureagenesis.
Original languageEnglish
Pages (from-to)1624-1636
Number of pages13
JournalHuman Mutation
Volume42
Issue number12
Early online date24 Sep 2021
DOIs
Publication statusPublished - Dec 2021

Keywords

  • intron
  • mutation analysis
  • N-acetylglutamate
  • N-acetylglutamate synthase
  • N-acetylglutamate synthase deficiency
  • noncoding sequence variants
  • regulatory element
  • urea cycle
  • urea cycle disorders
  • UREA-CYCLE ENZYMES
  • SYNTHETASE-I GENE
  • GLUCOCORTICOID-RECEPTOR
  • MONOLAYER-CULTURES
  • RAT-LIVER
  • DEFICIENCY
  • EXPRESSION
  • INDUCTION
  • ENHANCER
  • DEXAMETHASONE

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