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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Bachmann C, Krahenbuhl S, Colombo JP, Schubiger G, Jaggi KH, Tonz O (1981) N-acetylglutamate synthetase deficiency: a disorder of ammonia detoxification. N Engl J Med 304:543
Bachmann C, Krahenbuhl S, Colombo JP (1982a) Purification and properties of acetyl-CoA: L-glutamate N-acetyltransferase from human liver. Biochem J 205:123–127
Bachmann C, Colombo JP, Jaggi K (1982b) N-acetylglutamate synthetase (NAGS) deficiency: diagnosis, clinical observations and treatment. Adv Exp Med Biol 153:39–45
Bachmann C, Brandis M, Weissenbarth-Riedel E, Burghard R, Colombo J.P (1988) N-acetylglutamate synthetase deficiency, a second patient. J Inher Metab Dis 11:191–193
Burlina AB, Bachmann C, Wermuth B, Bordugo A, Ferrari V, Colombo JP, Zacchello F (1992) Partial N-acetylglutamate synthetase deficiency: a new case with uncontrollable movement disorders. J Inherit Metab Dis 15:395–398
Caldovic L, Morizono H, Yu X, Thompson M, Shi D, Gallegos R, Allewell NM, Malamy MH, Tuchman M (2002a) Identification, cloning and expression of the mouse N-acetylglutamate synthase gene. Biochem J 364:825–831
Caldovic L, Morizono H, Panglao M, Gallegos R, Yu X, Shi D, Malamy MH, Norma M. Allewell NM, Tuchman M (2002b) Cloning and expression of the human N-acetylglutamate synthase gene. Biochem Biophys Res Commun 299:581–586
Coude FX, Sweetman L, Nyhan WL (1979) Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia. J Clin Invest 64:1544–1551
Coude FX, Rabier D, Cathelineau L, Grimber G, Parvy P, Kamoun P (1982) A mechanism for valproate-induced hyperammonemia. Adv Exp Med Biol 153:153–161
Elpeleg ON, Colombo JP, Amir N, Bachmann C, Hurvitz H (1990) Late-onset form of partial N-acetylglutamate synthetase deficiency. Eur J Pediatr 149:634–636
Elpeleg O, Shaag A, Ben-Shalom E, Schmid T, Bachmann C (2002) N-acetylglutamate synthase deficiency and the treatment of hyperammonemic encephalopathy. Ann Neurol 52:845–849
Forget PP, Oosterhout M van, Bakker JA, Wermuth B, Vles JS, Spaapen LJ (1999) Partial N-acetyl-glutamate synthetase deficiency masquerading as a valproic acid-induced Reye-like syndrome. Acta Paediatr 88:1409–1411
Grisolia S, Cohen PP (1953) Catalytic role of glutamate derivatives in citrulline biosynthesis. J Biol Chem 204:753–757
Guffon N, Vianey-Saban C, Bourgeois J, Rabier D, Colombo JP, Guibaud P (1995) A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inherit Metab Dis 18:61–65
Hall LM, Metzenberg RL, Cohen PP (1958) Isolation and characterization of a naturally occurring cofactor of carbamyl phosphate biosynthesis. J Biol Chem 230:1013–1021
Hinnie J, Colombo JP, Wermuth B, Dryburgh FJ (1997) N-acetylglutamate synthetase deficiency responding to carbamylglutamate. J Inherit Metab Dis 20:839–838
Kim S, Paik WK, Cohen PP (1972) Ammonia intoxication in rats: protection by N-carbamoyl-L-glutamate plus L-arginine. Proc Natl Acad Sci USA 69:3530–3533
Marshall M, Metzenberg RL, Cohen PP (1958) Purification of carbamyl phosphate synthetase from frog liver. J Biol Chem 233:102–105
Meijer AJ, Lof C, Ramos IC, Verhoeven AJ (1985) Control of ureogenesis. Eur J Biochem 148:189–196
Morris AA, Richmond SW, Oddie SJ, Pourfarzam M, Worthington V, Leonard JV (1998) N-acetylglutamate synthetase deficiency: favourable experience with carbamylglutamate. J Inherit Metab Dis 21:867–840
Pandya AL, Koch R, Hommes FA, Williams JC (1991) N-acetylglutamate synthetase deficiency: clinical and laboratory observations. J Inherit Metab Dis 14:685–690
Plecko B, Erwa W, Wermuth B (1998) Partial N-acetylglutamate synthetase deficiency in a 13-year-old girl: diagnosis and response to treatment with N-carbamylglutamate. Eur J Pediatr 157:996–998
Schubiger G, Bachmann C, Barben P, Colombo JP, Tonz O, Schupbach D (1991) N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication. Eur J Pediatr 150:353–356
Shigesada K, Tatibana M (1971) Role of acetylglutamate in ureotelism. I. Occurrence and biosynthesis of acteylglutamate in mouse rat tissues. J Biol Chem 246:5588–5595
Sonoda T, Tatibana M (1983) Purification of N-acetyl-L-glutamate synthetase from rat liver mitochondria and substrate and activator specificity of the enzyme. J Biol Chem 258:9839–9844
Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M (1998) Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338:1352–1357
Takanashi J, Barkovich,A, Cheng S, Weisiger K, Ohnstad C, Mudge C, Rosenthal P, Tuchman M, Packman, S (2002) Brain MR imaging in neonatal hyperammonemic encephalopathy due to proximal urea cycle disorders. Am J Neuroradiol (in press)
Vockley J, Vockley CM, Lin SP, Tuchman M, Wu TC, Lin CY, Seashore MR (1992) Normal N-acetylglutamate concentration measured in liver from a new patient with N-acetylglutamate synthetase deficiency: physiologic and biochemical implications. Biochem Med Metab Biol 47:38–46
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