In order to clarify whether cystathionine beta-synthase (CBS) could differentiate groups of patients with various vascular diagnosis, CBS was studied in cultured human skin fibroblasts from 99 human subjects diagnosed as homozygotes or heterozygotes for CBS deficiency or suffering from atherosclerotic vascular disease or Down's syndrome (prone to less atherosclerosis).
Arteriosclerosis seems to be increased in heterozygotes as well (cystathionine beta-synthase gene dosage 50%) but rare in Down syndrome (cystathionine beta-synthase gene dosage 150%).
These in vitro studies support our hypothesis that enhanced metabolism of ara-C in DS cells may be a contributing factor to the superior survival rate of DS children with AML and is possibly based on a gene dosage effect of genes localized to chromosome 21 including cystathionine-beta-synthase.
We have shown that relative CBS transcripts were significantly higher in DS compared with non-DS myeloblasts, and CBS transcript levels correlated with in vitro ara-C sensitivity (J. W. Taub et al., Blood, 94: 1393-1400, 1999).
The dual purpose of the present study was to evaluate the impact of overexpression of the CBS gene on homocysteine metabolism in children with DS and to determine whether the supplementation of trisomy 21 lymphoblasts in vitro with selected nutrients would shift the genetically induced metabolic imbalance.
The results of this study with clinically relevant cell line models suggest potential mechanisms for disparate patterns of CBS gene expression in DS and non-DS myeloblasts and may, in part, explain the greater sensitivity to chemotherapy shown by patients with DS AML.
The results of this study with clinically relevant cell line models suggest potential mechanisms for disparate patterns of CBS gene expression in DS and non-DS myeloblasts and may, in part, explain the greater sensitivity to chemotherapy shown by patients with DS AML.
We therefore investigated expression levels of six proteins encoded on chromosome 21 (HACS1, DYRK1A, alphaA-crystallin, FTCD, GARS-AIRS-GART, and CBS) in fetal cerebral cortex from DS and controls at 18-19 weeks of gestational age using Western blot analysis.
In clinically relevant AML cell line models, high cystathionine-beta-synthase transcripts in DS CMK cells were accompanied by 10-fold greater ara-C sensitivity and 2.4-fold higher levels of ara-CTP compared with non-DS CMS cells.
The high event-free survival (EFS) rates of DS AML patients and in particular, patients with megakaryocytic leukemia (AMkL), at least in part reflects an increased sensitivity to cytosine arabinoside (ara-C) secondary to increased expression of the chromosome 21-localized gene, cystathionine-beta-synthase, and potentially global mechanisms which increase the susceptibility of cells to undergo apoptosis.
In the present study, we determined polymorphisms of MTHFR A222V (677C > T), MTHFR E429A (1298A > C), MTRR I22M (66A > G), MTR D919G (2756A > G), and CBS844ins68 and total plasma homocysteine levels (tHcy) among 154 mothers of children with Down syndrome (DS) and 158 control mothers from Brazil.
The purpose of the present study was to analyse these findings among the French population and to investigate whether common polymorphisms in genes of the folate and homocysteine pathway, including the MTHFR 677C > T, MTHFR 1298A > C, the methionine synthase (MTR) 2756A > G, the cystathionine beta-synthase (CBS) 844Ins68 and the reduced folate carrier (RFC-1) 80G > A polymorphisms, contribute to the risk of trisomy 21.
Taking into consideration that in the one-carbon metabolism cystathionine beta-synthase (CBS) catalyzes Hcy in an irreversible way, and that CBS gene is located in chromosome 21, fetuses and infants with DS have functional folate deficiency due to overexpression of CBS.
Paraoxonase-1 was up-regulated in Down syndrome fetal liver, while cystathionine beta synthase gene expression in Down syndrome fetuses was similar to the gene level in control fetuses.
The methionine-synthase-reductase A66G, the methionine-synthase A2756G and the cystathionine-beta-synthase844ins68 polymorphisms were not associated with increased risk of Down syndrome.
A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-beta-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is compromised.
In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10-methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1).
The results show that individual polymorphisms studied in this work are not associated with DS; however, the effects of the combined risk genotypes among MTR, MTRR, CBS and RFC genes are considered maternal risk factors for DS offspring in our population.