Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles.
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.
Caldovic
Ljubica
L
Children's Research Institute, Children's National Medical Center, The George Washington University, Washington, DC 20010, USA.
Morizono
Hiroki
H
Panglao
Maria G
MG
Lopez
Giselle Y
GY
Shi
Dashuang
D
Summar
Marshall L
ML
Tuchman
Mendel
M
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
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