Cystathionine beta synthase: Gene dosage effect in trisomy 21

Chadefaux, B.; Rethoré, M O; Raoul, O; Ceballos, I.; Poissonnier, M; Gilgenkranz, S.; Allard, Delphine

doi:10.1016/0006-291x(85)91641-9

Cited by 93 publications

(42 citation statements)

References 9 publications

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“…Interestingly, as early as 1977, it has already been observed that patients with Down's syndrome, who have three copies of chromosome 21, are almost free of atherosclerosis [7]. This has been attributed to the increased activity of CBS which has been shown later to be 166% in fibroblast cultures compared to controls [8]. This observation suggested an involvement of Hcy in atherogenesis.…”

mentioning

confidence: 96%

Molecular Genetics of Homocysteine Metabolism

Födinger

Buchmayer

Sunder‐Plassmann

1999

Mineral Electrolyte Metab

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Recent genetic studies have led to the characterization of molecular determinants contributing to the pathogenesis of hyperhomocysteinemia. In this article we summarize the current insights into the molecular genetics of severe, moderate and mild hyperhomocysteinemia. We will consider deficiencies of the trans-sulfuration enzyme cystathionine β-synthase (gene symbol: CBS), and the disturbances of the remethylation enzymes 5,10-methylenetetrahydrofolate reductase (gene symbol: MTHFR), methionine synthase (gene symbol: MTR), and the recently identified methionine synthase reductase (gene symbol: MTRR). Furthermore, we will focus on clinically important genetic polymorphisms which are highly prevalent and thus of potential general interest.

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mentioning

confidence: 96%

Molecular Genetics of Homocysteine Metabolism

Födinger

Buchmayer

Sunder‐Plassmann

1999

Mineral Electrolyte Metab

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“…A gene dosage effect could increase cystathionine-␤ -synthase, and thus reduce the supply of one-carbon units. Increased activity of this enzyme (possibly resulting from a gene dosage effect) has been suggested in the urine amino acid pattern in children with trisomy 21 and from fi broblast studies [15,16] . The effect might further enhance demand for one-carbon units, and therefore might also reduce FIGLU levels.…”

Section: Discussionmentioning

confidence: 96%

A Folate-Dependent Metabolite in Amniotic Fluid from Pregnancies with Normal or Trisomy 21 Chromosomes

Baggot

Eliseo²,

Kalamarides

et al. 2005

Fetal Diagn Ther

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Introduction: Previous studies have given conflicting results as to whether or not folate metabolism is altered in Down syndrome. Folate is necessary to facilitate metabolism of one-carbon units. Folate accepts one-carbon units from one-carbon unit donors, including formiminoglutamate (FIGLU). Folate deficiency leads to accumulation of FIGLU and impairment of one-carbon unit metabolism. FIGLU is a functional measure of folate deficiency. Materials and Methods: Archived anonymized amniotic fluid specimens were obtained from normal pregnancies and those with Down syndrome. Gas liquid chromatography/mass spectrometry was used to quantitate FIGLU, which is elevated in folate deficiency. A tetra-deuterated FIGLU was used as a standard, and single-ion monitoring was performed. Nonparametric statistical analysis was performed with the Mann-Whitney U test. Results: FIGLU was significantly lower in pregnancies with Down syndrome. The median FIGLU level was 0.9 µmol/l in amniotic fluid from fetuses with Down syndrome. The median FIGLU level was 1.3 in amniotic fluid from control fetuses. This difference was statistically significant (p = 0.009). No statistically significant differences were found with histidine or glutamate. Discussion: There was no evidence of folate deficiency. FIGLU was decreased, not increased. Decreased FIGLU might result from accelerated activity of one or more genes on chromosome 21, by a gene dosage effect. Genes which might explain the reduced FIGLU include one which degrades FIGLU (glutamate formiminotransferase-cyclodeaminase), one which participates in purine synthesis, and one which degrades homocysteine (cystathionine-β-synthase).

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“…Pathologies associated with aberrant H 2 S levels are probably under-reported. Subjects with trisomy 21 manifesting as Down syndrome produce high H 2 S levels, because the CBS gene is located at 21q22.3, and the H 2 S over-production is hypothesized to be responsible for the progressive mental retardation manifesting within the first year of life of Down syndrome subjects (13,48). Acute H 2 S intoxication leads to the loss of central respiratory drive, cytochrome c oxidase inhibition, glutathione depletion, reduction of ferric to ferrous ions, and reduction of O 2 to ROS (34).…”

Section: Sulfhydrationmentioning

confidence: 99%

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

Heneberg

2014

Antioxidants & Redox Signaling

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Significance: Redox modifications of thiols serve as a molecular code enabling precise and complex regulation of protein tyrosine phosphatases (PTPs) and other proteins. Particular gasotransmitters and even the redox modifications themselves affect each other, of which a typical example is S-nitrosylation-mediated protection against the further oxidation of protein thiols. Recent Advances: For a long time, PTPs were considered constitutively active housekeeping enzymes. This view has changed substantially over the last two decades, and the PTP family is now recognized as a group of tightly and flexibly regulated fundamental enzymes. In addition to the conventional ways in which they are regulated, including noncovalent interactions, phosphorylation, and oxidation, the evidence that has accumulated during the past two decades suggests that many of these enzymes are also modulated by gasotransmitters, namely by nitric oxide (NO) and hydrogen sulfide (H 2 S). Critical Issues: The specificity and selectivity of the methods used to detect nitrosylation and sulfhydration remains to be corroborated, because several researchers raised the issue of false-positive results, particularly when using the most widespread biotin switch method. Further development of robust and straightforward proteomic methods is needed to further improve our knowledge of the full extent of the gasotransmitters-mediated changes in PTP activity, selectivity, and specificity. Further Directions: Results of the hitherto performed studies on gasotransmitter-mediated PTP signaling await translation into clinical medicine and pharmacotherapeutics. In addition to directly affecting the activity of particular PTPs, the use of reversible S-nitrosylation as a protective mechanism against oxidative stress should be of high interest. Antioxid. Redox Signal. 20, 2191-2209.

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Cystathionine beta synthase: Gene dosage effect in trisomy 21

Cited by 93 publications

References 9 publications

Molecular Genetics of Homocysteine Metabolism

Molecular Genetics of Homocysteine Metabolism

A Folate-Dependent Metabolite in Amniotic Fluid from Pregnancies with Normal or Trisomy 21 Chromosomes

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

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