Is Absence of Atheroma in Down Syndrome Due to Decreased Homocysteine Levels?

Chadefaux, B.; Ceballos, I.; Hamet, M.; Coude, M.; Poissonnier, M; Kamoun, P.; Allard, Delphine

doi:10.1016/s0140-6736(88)90211-5

Cited by 55 publications

(29 citation statements)

References 6 publications

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“…28 Despite these relatively low levels, we found a significant association between IQ and t-Hcys. Several hypotheses may explain this association.…”

Section: Discussioncontrasting

confidence: 54%

Homocysteine and related genetic polymorphisms in Down's syndrome IQ

Anello

Bosco³

et al. 2005

Journal of Neurology, Neurosurgery & Psychiatry

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Objective: Down's syndrome (DS) is the most frequent genetic cause of Alzheimer-type dementia. Its metabolic phenotype involves an increased trans-sulphuration of homocysteine. The aim of the present study was to investigate the influence of homocysteinaemia (t-Hcys), folate, vitamin B 12 , and related polymorphisms on intelligence quotient (IQ) in DS. Methods: The IQ of 131 patients with trisomy 21 from a specialist centre in Sicily was determined and classified according to DMS-IV. The effects of age, folate, vitamin B 12 , t-Hcys, and genetic polymorphisms on IQ were evaluated separately and in combination using regression analyses. Results: IQ was significantly lower in DS patients with t-Hcys .7.5 mmol/l (median) and in those who were carriers of methylenetetrahydrofolate reductase (MTHFR) 677 T allele and of methylenetetrahydrofolate reductase 677 T and transcobalamin 776 G combined alleles (p = 0.0013, p = 0.0165, and p = 0.0074, respectively). The IQ correlated significantly with t-Hcys and folate in single and multiple regression analyses, independently of age. In addition, t-Hcys .9.6 mmol/l (upper quartile) was found to be associated with low IQ (,40, median of study group) with an odds ratio of 2.61 (p = 0.0203). The odds ratio was increased by threefold in carriers of MTHFR 677 T allele. The MTHFR 677 T allele/ transcobalamin 776 G allele combination was associated with the risk of DS patients to have an IQ less that the median with an odds ratio of 2.68 (95% CI 1.26 to 5.70, p = 0.0104). Conclusion: This study found evidence of an association between t-Hcys and MTHFR 677 T and transcobalamin 776 G alleles with IQ in patients with DS. The association may be related to a defective remethylation of homocysteine, affecting IQ.

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“…28 Despite these relatively low levels, we found a significant association between IQ and t-Hcys. Several hypotheses may explain this association.…”

Section: Discussioncontrasting

confidence: 54%

Homocysteine and related genetic polymorphisms in Down's syndrome IQ

Anello

Bosco³

et al. 2005

Journal of Neurology, Neurosurgery & Psychiatry

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“…21q22.3), and its overexpression has been suggested to be linked to certain of the phenotypic features of Down syndrome (DS). Elevated CBS expression in DS results in low plasma homocysteine compared with non-DS individuals and has been suggested to contribute to decreased atherosclerosis in DS patients (8). In our own studies of CBS and DS, we also found striking increases (ϳ12-fold) in CBS transcripts in myeloblasts from DS children with AML compared with non-DS myeloblasts (9).…”

supporting

confidence: 54%

“…3, A-D, lanes 6, 14, 28, and 38). With the exception of complex 11, these were all supershifted by antibodies to Sp1 and/or Sp3 (lanes 8,9,21,22,31,32,44, and 45). Complex 2 was partially competed by an Sp1 consensus oligonucleotide (lane 6) and partially supershifted by anti-Sp1 antibody (lane 8).…”

Section: Differential Binding Of Sp1/sp3 To the Cbs ϫ1bmentioning

confidence: 99%

Transcriptional Regulation of Cell-specific Expression of the Human Cystathionine β-Synthase Gene by Differential Binding of Sp1/Sp3 to the −1b Promoter

Matherly¹,

Taub²

2001

Journal of Biological Chemistry

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Cystathionine ␤-synthase (CBS) catalyzes the condensation of serine and homocysteine to form cystathionine, an intermediate step in the synthesis of cysteine. We previously characterized the CBS ؊1b minimal promoter (؊3792 to ؊3667) and found that Sp1/Sp3, nuclear factor Y, and USF-1 were involved in the regulation of basal promoter activity (Ge, Cystathionine ␤-synthase (CBS 1 ; EC 4.2.1.22), a pyridoxal 5Ј-phosphate-dependent enzyme involved in the transsulfuration pathway, catalyzes the condensation of L-serine and Lhomocysteine to form cystathionine, an intermediate step in the synthesis of cysteine. The human CBS gene product is a 63,000-Da polypeptide. The tetrameric protein is catalytically dependent on both heme and pyridoxal phosphate and is allosterically regulated by S-adenosylmethionine (1-4). The human CBS gene spans over 30 kilobases and consists of 23 exons ranging in size from 42 to 209 base pairs (5). The CBS polypeptide is encoded by exons 1-14 and 16. The human CBS gene encodes multiple mRNAs differing in their 5Ј-untranslated regions, resulting from the use of five alternative noncoding exons (designated Ϫ1a to Ϫ1e) and a constant exon 0. Transcripts containing exons Ϫ1a and Ϫ1b appear to be the most abundant and are found in an assortment of adult and fetal tissues (6). By contrast, use of exons Ϫ1c, Ϫ1d, and Ϫ1e appears to be rare. There are at least two GC-rich TATA-less promoters upstream of exons Ϫ1a and Ϫ1b, containing numerous putative transcription elements (Sp1 (specificity protein 1), AP1, AP2, etc.) (5, 6). In our recent study of the CBS Ϫ1b minimal promoter (mapping between positions Ϫ3792 and Ϫ3667), we demonstrated important transactivating roles for Sp1, Sp3, NF-Y, and USF-1 (7).YThe CBS gene has been localized to human chromosome 21 (e.g. 21q22.3), and its overexpression has been suggested to be linked to certain of the phenotypic features of Down syndrome (DS). Elevated CBS expression in DS results in low plasma homocysteine compared with non-DS individuals and has been suggested to contribute to decreased atherosclerosis in DS patients (8). In our own studies of CBS and DS, we also found striking increases (ϳ12-fold) in CBS transcripts in myeloblasts from DS children with AML compared with non-DS myeloblasts (9). Interestingly, this elevated CBS expression was associated with increased in vitro sensitivities to cytosine arabinoside (Ara-C) and generation of Ara-C triphosphate, likely due to downstream effects of CBS on endogenous folate and nucleotide pools (9 -12). This may explain, in part, the remarkably high event-free survival rates (70 -100%) and low relapse rates (Ͻ15%) of DS children with AML compared with non-DS children treated with Ara-C-based chemotherapy protocols. Increased CBS transcripts in DS over non-DS myeloblasts in-*

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“…The human CBS gene has been localized to chromosome 21 (21q22.3) and is overexpressed in the trisomy 21 of Down's patients (37,38). These patients have lower than normal plasma homocysteine (39). CBS knockout mice have also been produced (40).…”

Section: Discussionmentioning

confidence: 99%

Hormonal Regulation of Cystathionine β-Synthase Expression in Liver

Ratnam

Maclean

Jacobs

et al. 2002

Journal of Biological Chemistry

144

127

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Homocysteine metabolism is altered in diabetic patients. Cystathionine ␤-synthase (CBS), a key enzyme involved in the transsulfuration pathway, which irreversibly converts homocysteine to cysteine, catalyzes the condensation of serine and homocysteine to cystathionine. Studies in streptozotocin-induced diabetic rats have shown that CBS enzyme activity is elevated in the liver but not in the kidney, and this effect is reversed by insulin treatment. To determine whether these effects resulted from alterations at the level of gene transcription, CBS mRNA was measured in diabetic and insulin-treated diabetic rats. CBS mRNA levels were found to be markedly higher in streptozotocin-induced diabetic rat livers; these were reduced by insulin administration. In H4IIE cells, a rat hepatoma cell culture model, glucocorticoids increased the cellular levels of CBS enzyme protein and CBS mRNA; insulin inhibited this stimulatory effect. Treatment with insulin also decreased CBS levels in HepG2 cells, a human hepatoma cell line. Nuclear run-on experiments in the rat cells confirmed that stimulation of CBS gene expression by glucocorticoids and the inhibition by insulin occurred at the transcriptional level. Transient transfections of HepG2 cells with a CBS-1b promoter luciferase reporter construct showed that the promoter activity was decreased by 70% after insulin treatment. These results show that insulin has a direct role in regulating homocysteine metabolism. Altered insulin levels in diseases such as diabetes may influence homocysteine metabolism by regulating the hepatic transsulfuration pathway.Cystathionine ␤-synthase (CBS) 1 (EC 4.2.1.22) catalyzes the first committed step in cysteine biosynthesis, the irreversible condensation of homocysteine with serine to form cystathionine (1). Homocysteine, a sulfur-containing nonprotein amino acid, is an intermediate in the metabolism of methionine. It is at a metabolic crossroads between its synthesis from methionine and its removal through the transsulfuration or remethylation pathways (2). Two pyridoxal 5Ј-phosphate-dependent enzymes comprise the transsulfuration pathway: CBS, which catalyzes the condensation of serine and homocysteine to cystathionine, and cystathionine ␥-lyase, which catalyzes the formation of cysteine, ␣-ketobutyrate, and ammonia (3, 4). The regulation of CBS gene expression is important in a number of physiological situations. Feeding rats a high protein diet or a high methionine diet increases CBS activity (5). It is also known that flux through the transsulfuration pathway provides cysteine for glutathione synthesis, so that altered CBS levels may be of importance in oxidative stress (6). The well known sparing effect of cysteine on methionine requirements is mediated, at least in part, via alterations in CBS activity. Our own recent work shows that glucagon administration to rats increases hepatic CBS enzyme activity and mRNA levels (7). CBS enzyme deficiency, an autosomal recessively inherited disorder, is the leading cause of homocystinuria. Partial d...

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Is Absence of Atheroma in Down Syndrome Due to Decreased Homocysteine Levels?

Cited by 55 publications

References 6 publications

Homocysteine and related genetic polymorphisms in Down's syndrome IQ

Homocysteine and related genetic polymorphisms in Down's syndrome IQ

Transcriptional Regulation of Cell-specific Expression of the Human Cystathionine β-Synthase Gene by Differential Binding of Sp1/Sp3 to the −1b Promoter

Hormonal Regulation of Cystathionine β-Synthase Expression in Liver

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