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).
The methionine-synthase-reductase A66G, the methionine-synthase A2756G and the cystathionine-beta-synthase844ins68 polymorphisms were not associated with increased risk of Down syndrome.
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.
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.
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 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).
These results shed new light on the function of the CBS gene, and raise the interesting possibility that CBS overexpression might have an advantageous effect on some cognitive functions in DS.
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.
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%).
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 concluded that RFC-1 and CBS gene mutation alleles are related to Down syndrome, and women with mutation RFC-1 G80G, CBS C833C OR combined with RFC-1 A80G and CBS 833TT genotype increase the risk of Down syndrome in China.
In Down's syndrome there is evidence that increased gene expression coding for specific cystathionine beta-synthase translates directly into biochemical aberrations, which result in a biochemical and metabolic imbalance of the methyl status.
These results may allow us to better understand the role of the transsulfuration pathway and especially CBS overexpression in the metabolism of biogenic amines and the catecholamine catabolism in persons with trisomy 21.
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.
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 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).