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Cystathionine ?-synthase deficiency: Of mice and men.

ABSTRACT: Cystathionine ?-synthase (CBS) deficiency (Online Mendelian Inheritance in Man [OMIM] 236,200) is an autosomal recessive disorder that is caused by mutations in the CBS gene. It is the most common inborn error of sulfur metabolism and is the cause of classical homocystinuria, a condition characterized by very high levels of plasma total homocysteine and methionine. Although recognized as an inborn error of metabolism over 60years ago, these is still much we do not understand related to how this specific metabolic defect gives rise to its distinct phenotypes. To try and answer these questions, several groups have developed mouse models on CBS deficiency. In this article, we will review various mouse models of CBS deficiency and discuss how these mouse models compare to human CBS deficient patients.

SUBMITTER: Kruger WD

PROVIDER: S-EPMC5526210 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Cystathionine β-synthase deficiency: Of mice and men.

Kruger Warren D WD

Molecular genetics and metabolism 20170519 3

Cystathionine β-synthase (CBS) deficiency (Online Mendelian Inheritance in Man [OMIM] 236,200) is an autosomal recessive disorder that is caused by mutations in the CBS gene. It is the most common inborn error of sulfur metabolism and is the cause of classical homocystinuria, a condition characterized by very high levels of plasma total homocysteine and methionine. Although recognized as an inborn error of metabolism over 60years ago, these is still much we do not understand related to how this ...[more]

PMID: 28583326

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Project description:Hydrogen sulfide (H2S) has been proposed to exert pro- as well as anti-inflammatory effects in various models of critical illness. In this study, we compared bacterial lipopolysaccharide (LPS)?induced changes in inflammatory mediator production, indices of multiple organ injury and survival in wild?type (WT) mice and in mice with reduced expression of one of the three H2S?producing enzymes, cystathionine-?-lyase (CSE), cystathionine-?-synthase (CBS) or 3-mercaptopyruvate sulfurtransferase (3MST). Mice were injected intraperitoneally (i.p.) with LPS (10 mg/kg). After 6 h, the animals were sacrificed, blood and organs were collected and the following parameters were evaluated: blood urea nitrogen (BUN) levels in blood, myeloperoxidase (MPO) and malondialdehyde (MDA) in the lung, cytokine levels in plasma and the expression of the three H2S?producing enzymes (CBS, CSE and 3MST) in the spleen, lung, liver and kidney. LPS induced a tissue?dependent upregulation of some of the H2S?producing enzymes in WT mice (upregulation of CBS in the spleen, upregulation of 3MST in the liver and upregulation of CBS, CSE and 3MST in the lung). Moreover, LPS impaired glomerular function, as evidenced by increased BUN levels. Renal impairment was comparable in the CSE?/? and ?3MST mice after LPS challenge; however, it was attenuated in the CBS+/? mice. MPO levels (an index of neutrophil infiltration) and MDA levels (an index of oxidative stress) in lung homogenates were significantly increased in response to LPS; these effects were similar in the WT, CBS+/?, CSE?/? and ?3MST mice; however, the MDA levels tended to be lower in the CBS+/? and CSE?/? mice. LPS induced significant increases in the plasma levels of multiple cytokines [tumor necrosis factor (TNF)?, interleukin (IL)?1?, IL?6, IL?10, IL?12 and interferon (IFN)?] in plasma; TNF?, IL?10 and IL?12 levels tended to be lower in all three groups of animals expressing lower levels of H2S?producing enzymes. The survival rates after the LPS challenge did not show any significant differences between the four animal groups tested. Thus, the findings of this study indicate that a deficiency in 3MST does not significantly affect endotoxemia, while a deficiency in CBS or CSE slightly ameliorates the outcome of LPS-induced endotoxemia in vivo.

Dataset Information

Cystathionine ?-synthase deficiency: Of mice and men.

Publications

Cystathionine β-synthase deficiency: Of mice and men.

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