Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases

Hum Mutat. 2009 Jan;30(1):56-60. doi: 10.1002/humu.20813.


The urea cycle is the primary means of nitrogen metabolism in humans and other ureotelic organisms. There are five key enzymes in the urea cycle: carbamoyl-phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1). Additionally, a sixth enzyme, N-acetylglutamate synthase (NAGS), is critical for urea cycle function, providing CPS1 with its necessary cofactor. Deficiencies in any of these enzymes result in elevated blood ammonia concentrations, which can have detrimental effects, including central nervous system dysfunction, brain damage, coma, and death. Functional variants, which confer susceptibility for disease or dysfunction, have been described for enzymes within the cycle; however, a comprehensive screen of all the urea cycle enzymes has not been performed. We examined the exons and intron/exon boundaries of the five key urea cycle enzymes, NAGS, and two solute carrier transporter genes (SLC25A13 and SLC25A15) for sequence alterations using single-stranded conformational polymorphism (SSCP) analysis and high-resolution melt profiling. SSCP was performed on a set of DNA from 47 unrelated North American individuals with a mixture of ethnic backgrounds. High-resolution melt profiling was performed on a nonoverlapping DNA set of either 47 or 100 unrelated individuals with a mixture of backgrounds. We identified 33 unarchived polymorphisms in this screen that potentially play a role in the variation observed in urea cycle function. Screening all the genes in the pathway provides a catalog of variants that can be used in investigating candidate diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ammonia / blood
  • Arginase / genetics
  • Argininosuccinate Lyase / genetics
  • Argininosuccinate Synthase / deficiency
  • Argininosuccinate Synthase / genetics
  • Argininosuccinic Aciduria
  • Carbamoyl-Phosphate Synthase (Ammonia) / deficiency
  • Carbamoyl-Phosphate Synthase (Ammonia) / genetics
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Humans
  • Hyperargininemia
  • Ornithine Carbamoyltransferase / genetics
  • Ornithine Carbamoyltransferase Deficiency Disease
  • Polymorphism, Single-Stranded Conformational
  • Urea / metabolism*


  • Ammonia
  • Urea
  • Ornithine Carbamoyltransferase
  • Arginase
  • Argininosuccinate Lyase
  • Carbamoyl-Phosphate Synthase (Ammonia)
  • Argininosuccinate Synthase