Abstract
Deficiency of the hepatic enzyme carbamoyl-phosphate synthase I (CPSI), results in lethal or near-lethal hyperammonaemia. As part of our work on CPSI deficiency we have explored the development of markers for prenatal diagnosis, and the determination of molecular defects resulting in CPSI deficiency. We have determined a set of highly informative microsatellite markers flanking the CPSI gene. We have found 14 mutations in individuals with CPSI deficiency. During our mutation studies, we have made extensive use of cell lines not normally expressing CPSI through amplification of 'illegitimate' transcripts. We summarize these findings and review our current understanding of this important enzyme.
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REFERENCES
Batshaw ML (1994) Inborn errors of urea synthesis (Review). Ann Neurol 35: 133–141.
Brusilow SW (1985) Disorders of the urea cycle. Hosp Prac (Office Ed) 20: 65–72.
de Groot CJ, van Zonneveld AJ, Mooren PG et al (1984) Regulation of mRNA levels of rat liver carbamoylphosphate synthetase by glucocorticosteroids and cyclic AMP as estimated with a specific cDNA. Biochem Biophys Res Commun 124: 882–888.
Guillou F, Liao M, Garcia-Espana A, Lusty CJ (1992) Mutational analysis of carbamyl phosphate synthetase. Substitution of Glu841 leads to loss of functional coupling between the two catalytic domains of the synthetase subunit. Biochemistry 31: 1656–1664.
Jackson MJ, Beaudet AL, O'Brien WE (1986) Mammalian urea cycle enzymes (Review). Annu Rev Genet 20: 431–464.
Lagace M, Howell BW, Burak R, Lusty CJ, Shore GC (1987) Rat carbamyl-phosphate synthetase I gene. Promoter sequence and tissue-specific transcriptional regulation in vitro. J Biol Chem 262: 10415–10418.
Liu Q, Sommer SS (1995) Restriction endonuclease fingerprinting (REF): a sensitive method for screening mutations in long, contiguous segments of DNA. Biotechniques 18(3): 470–477.
Lusty CJ, Liao M (1993) Substitution of Glu841 by lysine in the carbamate domain of carbamyl phosphate synthetase alters the catalytic properties of the glutaminase subunit. Biochemistry 32: 1278–1284.
McReynolds JW, Crowley B, Mahoney MJ, Rosenberg LE (1981) Autosomal recessive inheritance of human mitochondrial carbamyl phosphate synthetase deficiency. Am J Hum Genet 33: 345–353.
Moorman AF, de Boer PA, Das AT et al (1990) Expression patterns of mRNAs for ammonia-metabolizing enzymes in the developing rat: the ontogenesis of hepatocyte heterogeneity. Histochem J 22: 457–468.
Niu B, Wang Z, Yu Y et al (1991) Functional analysis of the CPS I upstream sequences with a cat assay. Chinese Med Sci J 6: 208–211.
Nyunoya H, Broglie KE, Widgren EE, Lusty CJ (1985a) The gene coding for carbamoyl-phosphate synthetase I was formed by fusion of an ancestral glutaminase gene and a synthetase gene. Proc Natl Acad Sci USA 82: 2244–2246.
Nyunoya H, Broglie KE, Lusty CJ (1985b) Characterization and derivation of the gene coding for mitochondrial carbamyl phosphate synthetase I of rat. J Biol Chem 260: 9346–9356.
Powers-Lee SG, Corina K (1986) Domain structure of rat liver carbamoyl phosphate synthetase I. J Biol Chem 261: 15349–15352.
Powers-Lee S, Corina K (1987) Photoaffinity labeling of rat liver carbamoyl phosphate synthetase I by 8-azido-ATP. J Biol Chem 262: 9052–9056.
Raiha N, Suihkonen J (1968) Development of urea-synthesizing enzymes in human liver. Acta Paediatr Scand 57: 121–127.
Rubio V (1993) Structure-function studies in carbamoyl phosphate synthetases (Review). Biochem Soc T rans 21: 198–202.
Rubio V, Grisolia S (1981) Human carbamoylphosphate synthetase I (Review). Enzyme 26: 233–239.
Rubio V, Ramponi G, Grisolia S (1981) Carbamoyl phosphate synthetase I of human liver. Purification, some properties and immunological cross-reactivity with the rat liver enzyme. Biochim Biophys Acta 659: 150–160.
Summar ML, Dasouki MJ, Schofield PJ et al (1995) Physical and linkage mapping of human carbamyl phosphate synthetase I (CPS1) and reassignment from 2p to 2q35. Cytogene Cell Genet 71: 266–268.
van den Hoff MJ, van de Zande LP, Dingemanse MA et al (1995) Isolation and characterization of the rat gene for carbamoylphosphate synthetase I. Eur J Biochem 228: 351–361.
Vasudevan S, Qureshi IA, Lambert M et al (1995) Nucleotide pool imbalances in the livers of patients with urea cycle disorders associated with increased levels of orotic aciduria. Biochem Mol Biol Int 35: 685–690.
Wong LJ, Craigen WJ, O'Brien WE (1994) Postpartum coma and death due to carbamoyl-phosphate synthetase I deficiency. Ann Intern Med 120: 216–217.
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Summar, M.L. Molecular genetic research into carbamoyl-phosphate synthase I: Molecular defects and linkage markers. J Inherit Metab Dis 21 (Suppl 1), 30–39 (1998). https://doi.org/10.1023/A:1005349306311
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DOI: https://doi.org/10.1023/A:1005349306311