Article

Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia

Children's Research Institute, Children's National Medical Center, The George Washington University, 111 Michigan Avenue NW, Washington, DC 20010, USA.
Human Genetics (Impact Factor: 4.52). 04/2003; 112(4):364-8. DOI: 10.1007/s00439-003-0909-5
Source: PubMed

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.

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    ABSTRACT: N-acetylglutamate synthase (NAGS) cat-alyzes the conversion of glutamate and acetyl-CoA to NAG, the essential allosteric activator of carbamyl phos-phate synthetase I, the first urea cycle enzyme in mam-mals. A 17-year-old female with recurrent hyperammone-mia attacks, the cause of which remained undiagnosed for 8 years in spite of multiple molecular and biochemi-cal investigations, showed markedly enhanced ureagenesis (measured by isotope incorporation) in response to N-carbamylglutamate (NCG). This led to sequencing of the regulatory regions of the NAGS gene and identification of a deleterious single-base substitution in the upstream enhancer. The homozygous mutation (c.-3064C>A), af-fecting a highly conserved nucleotide within the hepatic nuclear factor 1 (HNF-1) binding site, was not found in single nucleotide polymorphism databases and in a screen of 1,086 alleles from a diverse population. Functional as-says demonstrated that this mutation decreases transcrip-tion and binding of HNF-1 to the NAGS gene, while a consensus HNF-1 binding sequence enhances binding to HNF-1 and increases transcription. Oral daily NCG ther-apy restored ureagenesis in this patient, normalizing her biochemical markers, and allowing discontinuation of al-ternate pathway therapy and normalization of her diet with no recurrence of hyperammonemia. Hum Mutat 32:1153–1160, 2011. C 2011 Wiley-Liss, Inc.
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    Human Mutation 01/2007; 28:754-759. · 5.05 Impact Factor