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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Acknowledgements
We thank Dr. Michael Malamy and the Tufts University Sequencing Service for their help with this study, and Kara Weisiger, Carol Ohnstad, Christine Mudge, and Dr. Philip Rosenthal for their clinical care of two of the patients. This work was supported by Public Health Service grants from the National Institute of Diabetes Digestive and Kidney Diseases (no. DK47870), the National Institute of Child Health and Human Development (nos. HD32652 and HD40677), and the General Clinical Research Center Program of the National Center for Research Resources. (nos. RR13297 and RR01271).
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Caldovic, L., Morizono, H., Panglao, M.G. et al. Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet 112, 364–368 (2003). https://doi.org/10.1007/s00439-003-0909-5
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DOI: https://doi.org/10.1007/s00439-003-0909-5