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

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 B⁰AT1 transporter and Met has the highest substrate affinity for B⁰AT1 than other neutral amino acids, hypermethioninemia may cause hyperexcretion of neutral amino acids.