Submitted on August 13, 2007
Accepted on October 8, 2007
The interaction between murine spf-ash mutation and genetic background yield different metabolic phenotypes
Juan C Marini1*, Ayelet Erez2, Leticia Castillo3, and Brendan Lee4
1 Pediatrics, Baylor College of Medicine, Houston, Texas, United States
2 Molecular and human genetics, Baylor College of Medicine, Houston, Texas, United States
3 Pediatrics, Division of Critical Care, Baylor College of Medicine, Houston, Texas, United States
4 Dept. of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: marini{at}bcm.edu.
The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week old wild type control and spf-ash mutant male mice from different genetic backgrounds (B6 and ICR) were infused intravenously with [13C18O]urea, L-[15N2]arginine, L-[5,5 D2]ornithine, L-[6-13C, 4,4,5,5, D4]citrulline and L-[ring-D5]phenylalanine to investigate the interaction between genetic background and spf-ash mutation on ureagenesis, arginine metabolism and nitric oxide production. ICRspf-ash mice maintained ureagenesis (5.5±0.3mmo·kg-1·h-1) and developed mild hyperammonemia (145±19 µmol/L) when an unbalanced nitrogen load was imposed; however, B6spf-ash mice became hyperammonemic (671±15 µmol/L) due to compromised ureagenesis (3.4±0.1 mmo·kg-1·h-1). Ornithine supplementation restored ureagenesis and mitigated hyperammonemia. A reduction in citrulline entry rate was observed due to the mutation in both genetic backgrounds (wild-type: 128, spf-ash: 60; SEM 4.0 µmol·kg-1·h-1). Arginine entry rate was only reduced in B6spf-ash mice (B6spf-ash: 332, ICRspf-ash: 453; SEM 20.6 µmol·kg-1·h-1). Genetic background and mutation had an effect on nitric oxide production (B6: 3.4, B6spf-ash: 2.8, ICR: 9.0, ICRspf-ash: 4.6, SEM 0.7 µmol·kg-1·h-1). Protein breakdown was the main source of arginine during the postabsorptive state and was higher in ICRspf-ash than in B6spf-ash mice (phenylalanine entry rate 479 and 327, respectively; SEM 18 µmol·kg-1·h-1). Our results highlight the importance of the interaction between mutation and genetic background on ureagenesis, arginine metabolism and nitric oxide production. These observations help explain the wide phenotypic variation of ornithine transcarbamylase deficiency in the human population.
