Neutral aminoaciduria in cystathionine β-synthase-deficient mice; an animal model of homocystinuria.

Abstract

The kidney is one of the major loci for the expression of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). While CBS-deficient (Cbs(-/-)) mice display homocysteinemia/methioninemia and severe growth retardation, and rarely survive beyond the first 4 wk, CTH-deficient (Cth(-/-)) mice show homocysteinemia/cystathioninemia but develop with no apparent abnormality. This study examined renal amino acid reabsorption in those mice. Although both 2-wk-old Cbs(-/-) and Cth(-/-) mice had normal renal architecture, their serum/urinary amino acid profiles largely differed from wild-type mice. The most striking feature was marked accumulation of Met and cystathionine in serum/urine/kidney samples of Cbs(-/-) and Cth(-/-) mice, respectively. Levels of some neutral amino acids (Val, Leu, Ile, and Tyr) that were not elevated in Cbs(-/-) serum were highly elevated in Cbs(-/-) urine, and urinary excretion of other neutral amino acids (except Met) was much higher than expected from their serum levels, demonstrating neutral aminoaciduria in Cbs(-/-) (not Cth(-/-)) mice. Because the bulk of neutral amino acids is absorbed via a B(0)AT1 transporter and Met has the highest substrate affinity for B(0)AT1 than other neutral amino acids, hypermethioninemia may cause hyperexcretion of neutral amino acids.

• Authors: Noriyuki Akahoshi, Shotaro Kamata, Masashi Kubota, Takako Hishiki, Yoshiko Nagahata, Tomomi Matsuura, Chiho Yamazaki, Yuka Yoshida, Hidenori Yamada, Yasuki Ishizaki, Makoto Suematsu, Tadashi Kasahara, Isao Ishii
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 306 Issue 12 Pg. F1462-76 (Jun 15 2014) ISSN: 1522-1466 [Electronic] United States
• PMID: 24761004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• Amino Acids, Neutral
• Cystathionine
• Methionine
• Cystathionine beta-Synthase
• Cystathionine gamma-Lyase

Topics

• Amino Acids, Neutral (metabolism)
• Animals
• Comorbidity
• Cystathionine (metabolism)
• Cystathionine beta-Synthase (deficiency, genetics, metabolism)
• Cystathionine gamma-Lyase (deficiency, genetics)
• Disease Models, Animal
• Female
• Homocystinuria (epidemiology, metabolism)
• Hyperhomocysteinemia (metabolism)
• Kidney Tubules, Proximal (pathology)
• Male
• Methionine (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Renal Aminoacidurias (epidemiology, metabolism)