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

  • Noriyuki Akahoshi
    Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
  • Shotaro Kamata
    Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan
  • Masashi Kubota
    Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan
  • Takako Hishiki
    Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan;
  • Yoshiko Nagahata
    Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan;
  • Tomomi Matsuura
    Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan;
  • Chiho Yamazaki
    Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
  • Yuka Yoshida
    Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
  • Hidenori Yamada
    Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
  • Yasuki Ishizaki
    Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;
  • Makoto Suematsu
    Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan;
  • Tadashi Kasahara
    Department of Biochemistry, Keio University Graduate School of Pharmaceutical Sciences, Tokyo, Japan
  • Isao Ishii
    Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan;

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<jats:p>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<jats:sup>−/−</jats:sup>) mice display homocysteinemia/methioninemia and severe growth retardation, and rarely survive beyond the first 4 wk, CTH-deficient ( Cth<jats:sup>−/−</jats:sup>) 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<jats:sup>−/−</jats:sup>and Cth<jats:sup>−/−</jats:sup>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<jats:sup>−/−</jats:sup>and Cth<jats:sup>−/−</jats:sup>mice, respectively. Levels of some neutral amino acids (Val, Leu, Ile, and Tyr) that were not elevated in Cbs<jats:sup>−/−</jats:sup>serum were highly elevated in Cbs<jats:sup>−/−</jats:sup>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<jats:sup>−/−</jats:sup>(not Cth<jats:sup>−/−</jats:sup>) mice. Because the bulk of neutral amino acids is absorbed via a B<jats:sup>0</jats:sup>AT1 transporter and Met has the highest substrate affinity for B<jats:sup>0</jats:sup>AT1 than other neutral amino acids, hypermethioninemia may cause hyperexcretion of neutral amino acids.</jats:p>

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