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Late onset N‐acetylglutamate synthase deficiency caused by hypomorphic alleles
Author(s) -
Caldovic Ljubica,
Morizono Hiroki,
Panglao Maria G.,
Lopez Giselle Y.,
Shi Dashuang,
Summar Marshall L.,
Tuchman Mendel
Publication year - 2005
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20146
Subject(s) - hyperammonemia , biology , atp synthase , mutant , urea cycle , enzyme , biochemistry , allele , cofactor , medicine , endocrinology , genetics , gene , amino acid , arginine
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. Hum Mutat 25:293–298, 2005. © 2005 Wiley‐Liss, Inc.