title: Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia.
abstract: N-acetylglutamate synthase (NAGS) is a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate, an essential allosteric activator of carbamyl phosphate synthetase I, the first enzyme of the urea cycle. Liver NAGS deficiency has previously been found in a small number of patients with hyperammonemia. The mouse and human NAGS genes have recently been cloned and expressed in our laboratory. We searched for mutations in the NAGS gene of two families with presumed NAGS deficiency. The exons and exon/intron boundaries of the NAGS gene were sequenced from genomic DNA obtained from the parents of an infant from the Faroe Islands who died in the neonatal period and from two Hispanic sisters who presented with acute neonatal hyperammonemia. Both parents of the first patient were found to be heterozygous for a null mutation in exon 4 (TGG-->TAG, Trp324Ter). Both sisters from the second family were homozygous for a single base deletion in exon 4 (1025delG) causing a frameshift and premature termination of translation. The finding of deleterious mutations in the NAGS gene confirms the genetic origin of NAGS deficiency. This disorder can now be diagnosed by DNA testing allowing for carrier detection and prenatal diagnosis.
authors.affiliation: Children's Research Institute, Children's National Medical Center, The George Washington University, 111 Michigan Avenue NW, 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 Gracia
authors.initials: MG
authors.lastname: Panglao
authors.forename: Sabrina F
authors.initials: SF
authors.lastname: Cheng
authors.forename: Seymour
authors.initials: S
authors.lastname: Packman
authors.forename: Mendel
authors.initials: M
authors.lastname: Tuchman
mesh_terms: D000123:Acetyltransferases / Q000235:genetics*; D000225:Adenine; D051046:Amino-Acid N-Acetyltransferase; D001483:Base Sequence; D003718:Denmark / Q000208:ethnology; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology* / Q000235:genetics; D006147:Guanine; D006630:Hispanic or Latino / Q000235:genetics; D006720:Homozygote; D006801:Humans; D022124:Hyperammonemia / Q000201:enzymology* / Q000208:ethnology / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D017422:Sequence Analysis, DNA; D014364:Tryptophan / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D006147:Guanine; D014364:Tryptophan; D000123:Acetyltransferases; D051046:Amino-Acid N-Acetyltransferase; C494874:NAGS protein, human; D000225:Adenine