Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes

Area of Science:

• Biochemistry
• Genetics
• Physiology

Background:

• The spf-ash mutation in mice impairs hepatic and intestinal ornithine transcarbamylase activity.
• Reduced enzyme activity leads to hyperammonemia and impaired ureagenesis, particularly under nitrogen load.

Purpose of the Study:

• To investigate the interaction between the spf-ash mutation and genetic background (B6 vs. ICR) on ureagenesis, arginine metabolism, and nitric oxide production.
• To understand the phenotypic variability of ornithine transcarbamylase deficiency.

Main Methods:

• Intravenous infusion of stable isotope-labeled compounds (urea, arginine, ornithine, citrulline, phenylalanine) in wild-type and spf-ash mutant mice from B6 and ICR backgrounds.
• Measurement of ureagenesis, arginine and citrulline entry rates, nitric oxide production, and protein breakdown.

Main Results:

• B6(spf-ash) mice exhibited severe hyperammonemia and compromised ureagenesis, unlike ICR(spf-ash) mice which maintained ureagenesis with mild hyperammonemia.
• Ornithine supplementation normalized ureagenesis and reduced hyperammonemia.
• Citrulline entry rate was reduced in spf-ash mice regardless of background, while arginine entry rate was reduced only in B6(spf-ash) mice.
• Nitric oxide production varied significantly between genetic backgrounds and mutation status.
• Protein breakdown was a major arginine source, higher in ICR(spf-ash) mice.

Conclusions:

• Genetic background significantly modulates the phenotypic expression of the spf-ash mutation.
• The interplay between genetic background and mutation is crucial for ureagenesis, arginine metabolism, and nitric oxide production.
• These findings provide insights into the variable presentation of ornithine transcarbamylase deficiency in humans.