title: Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles.
abstract: N-acetylglutamate (NAG) is a unique cofactor that is essential for the conversion of ammonia to urea in the liver. N-acetylglutamate synthase (NAGS) catalyzes the formation of NAG. Deficiency of NAGS causes a block in ureagenesis resulting in hyperammonemia. Although a number of mutations have been identified in the NAGS gene, their effects on NAGS enzymatic activity have not been examined. We describe here three mutations in two families with NAGS deficiency. Studies of the purified recombinant mutant proteins revealed deleterious effects on NAGS affinity for substrates, and on the rate of catalysis. These studies provide a better understanding of the function of NAGS, and the mechanisms for deleterious effect of mutations causing inherited NAGS deficiency.
authors.affiliation: Children's Research Institute, Children's National Medical Center, The George Washington University, Washington, DC 20010, USA.
authors.forename: Ljubica
authors.initials: L
authors.lastname: Caldovic
authors.forename: Hiroki
authors.initials: H
authors.lastname: Morizono
authors.forename: Maria G
authors.initials: MG
authors.lastname: Panglao
authors.forename: Giselle Y
authors.initials: GY
authors.lastname: Lopez
authors.forename: Dashuang
authors.initials: D
authors.lastname: Shi
authors.forename: Marshall L
authors.initials: ML
authors.lastname: Summar
authors.forename: Mendel
authors.initials: M
authors.lastname: Tuchman
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D051046:Amino-Acid N-Acetyltransferase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000818:Animals; D001926:Brain Death; D002384:Catalysis; D002648:Child; D016384:Consensus Sequence; D004252:DNA Mutational Analysis; D004044:Dietary Proteins / Q000009:adverse effects / Q000493:pharmacokinetics; D017809:Fatal Outcome; D005260:Female; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D022124:Hyperammonemia / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D007231:Infant, Newborn; D007859:Learning Disabilities / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009104:Multiple Trauma / Q000601:surgery; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D017354:Point Mutation; D011183:Postoperative Complications; D022821:RNA Splice Sites / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014508:Urea / Q000378:metabolism; D014714:Vertebrates / Q000235:genetics
chemical_list: D004044:Dietary Proteins; D005971:Glutamates; D022821:RNA Splice Sites; D011993:Recombinant Fusion Proteins; D018698:Glutamic Acid; D014508:Urea; D051046:Amino-Acid N-Acetyltransferase; C494874:NAGS protein, human; C016195:N-acetylglutamic acid