NAGS variants don't synthesize N-acetylglutamate

Stable Identifier
R-HSA-9955697
Type
Reaction [transition]
Species
Homo sapiens
Compartment
mitochondrial matrix
ReviewStatus
3/5
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NAGS variants don't synthesize N-acetylglutamate
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NAGS deficiency (NAGSD, OMIM 23710) is an autosomal recessive disorder that arises due to mutations in the N-acetylglumate synthase (NAGS) gene that catalyzes the production of N-acetylglutamate (NAG) from acetyl-CoA and glutamate (reviewed in Kenneson and Singh, 2020). NAGS is a necessary allosteric activator of the urea cycle enzyme CPS1; in consequence, disease-causing mutations in NAGS and CPS1 lead to phenotypes that are essentially indistinguishable biochemically and clinically. NAGSD and CPS1D are characterized by hyperammonemia due to defects in the ability to convert toxic ammonia to urea, causing lethargy, vomiting, seizures, coma and neurological damage (reviewed in Kenneson and Singh, 2020). Clinically, NAGSD may present neonatally or later in development, with alleles associated with delayed onset generally being less detrimental to enzyme function.
The following variants are annotated as causing NAGS deficiency, either as candidates or members depending on the levels of experimental evidence available. These variants are classified by ClinVar as either pathogenic or likely pathogenic:

Candidates:
NAGS C200R (Schmidt et al, 2005)
NAGS L312P (Caldovic et al, 2007)
NAGS W324* (Haberle, Schmidt et al, 2003)
NAGS S410P (Schmidt et al, 2005)
NAGS T431I (Caldovic et al, 2005; Caldovic et al, 2007)
NAGS R509Q (Caldovic et al, 2005)
NAGS A518T (Schmidt et al, 2005)

Members:
NAGS A279T (Haberle, Schmidt et al, 2003)
NAGS L430P (Haberle, Schmidt et al, 2003; Schmidt et al, 2005)
NAGS E433D (Haberle, Schmidt et al, 2003; Caldovic et al, 2007)
NAGS W484R (Caldovic et al, 2007)
Literature References
PubMed ID Title Journal Year
17421020 Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene

Caldovic, L, Morizono, H, Tuchman, M

Hum Mutat 2007
15878741 Identification of novel mutations of the human N-acetylglutamate synthase gene and their functional investigation by expression studies

Schmidt, E, Nuoffer, JM, Häberle, J, Pauli, S, Guffon, N, Vianey-Saban, C, Wermuth, B, Koch, HG

Biochim Biophys Acta 2005
33036647 Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature

Kenneson, A, Singh, RH

Orphanet J Rare Dis 2020
15714518 Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles

Caldovic, L, Morizono, H, Panglao, MG, Lopez, GY, Shi, D, Summar, ML, Tuchman, M

Hum Mutat 2005
12754705 Mutation analysis in patients with N-acetylglutamate synthase deficiency

Häberle, J, Schmidt, E, Pauli, S, Kreuder, JG, Plecko, B, Galler, A, Wermuth, B, Harms, E, Koch, HG

Hum Mutat 2003
Participants
Input
Participates
as an event of
Catalyst Activity

L-glutamate N-acetyltransferase activity of NAGS variant dimers [mitochondrial matrix]

Physical Entity
NAGS variant dimers [mitochondrial matrix] (Homo sapiens)
Activity
L-glutamate N-acetyltransferase activity (GO:0004042)
This event is regulated
Positively by
Regulator
L-Arg [mitochondrial matrix]
Normal reaction
glutamate + acetyl CoA => N-acetyl glutamate + CoA (Homo sapiens)
Functional status

Loss of function of NAGS variant dimers [mitochondrial matrix]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
N-acetylglutamate synthase deficiency DOID:0112258 NAG synthetase deficiency, NAGS deficiency, N-acetylglutamate synthetase deficiency, N-acetyl glutamate synthetase deficiency, hyperammonemia due to N-acetylglutamate synthase deficiency
Cross References
Mondo
Authored
Rothfels, K  (2025-07-02)
Created
Rothfels, K  (2025-06-11)
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