We conclude that hyperhomocysteinemia is associated with a decreased activity and expression of CBS in renal PTs because of the defect of chromosome 13 in SS rats.
Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS) genes, involved in the intracellular metabolism of homcysteine, can result in hyperhomocysteinemia.
Twelve-week-old male CBS<sup>+/-</sup> (a model of HHcy) and sibling CBS<sup>+/+</sup> (WT) mice were treated with SG1002 (a slow release H<sub>2</sub>S donor) diet for 4 months.
In contrast to the previous report, which assumed that the 68-bp insertion introduced a premature-termination codon and resulted in a nonfunctional CBS enzyme, we found that the presence of this mutation is not associated with hyperhomocysteinemia.
Severe HHcy (plasma Hcy 210 micromol/L) accelerates spontaneous arthrosclerosis in the CBS(-/-)/apoE(-/-) mice, reduces the concentration of circulating HDL, apoA-I, and large HDL particles, inhibits HDL function, and enhances HDL-C clearance.
Redox homeostasis, free-radical detoxification and one-carbon metabolism (Methionine-Hcy-Folate cycle) require CBS and its deficiency leads to hyperhomocysteinemia (HHcy) causing retinovascular thromboembolism and eye-lens dislocation along with vascular cognitive impairment and dementia.
Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.34-0.99)].
To study Hyperhomocysteinemia (HHcy)-induced epigenetic modifications as potential mechanisms of blood retinal barrier (BRB) dysfunction, retinas isolated from three- week-old mice with elevated level of Homocysteine (Hcy) due to lack of the enzyme cystathionine β-synthase (<i>cbs<sup>-/-</sup></i> , <i>cbs<sup>+/-</sup></i> and <i>cbs<sup>+/+</sup></i> ), human retinal endothelial cells (HRECs), and human retinal pigmented epithelial cells (ARPE-19) treated with or without Hcy were evaluated for (1) histone deacetylases (HDAC), (2) DNA methylation (DNMT), and (3) miRNA analysis.
Cystathionine-beta-synthase (CBS) is an enzyme that catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine, and in which variations are associated with human hyperhomocysteinemia and homocystinuria.
Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) and cystathionine beta-synthase (CBS) genes, involved in the intracellular metabolism of homocysteine (Hcy), can result in hyperhomocysteinemia.
These results highlighted that deficiency of CBS activity was correlated with the nitration of CBS at Tyr<sup>163</sup>, Tyr<sup>223</sup>, Tyr<sup>381</sup> and Tyr<sup>518</sup>, which may play a mutual role in the progression of HHcy.
Stratified analysis by sex found that lower CBS methylation levels were associated with a 2.128-fold increased risk for treatment failure in males with HHcy.
Here we show that plasma Hcy-thiolactone is elevated 59-fold and 72-fold in human patients with hyperhomocysteinemia secondary to mutations in methylenetetrahydrofolate reductase and cystathionine beta-synthase genes, respectively.
The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.
In vitro study also shows that HMD induced hyperhomocysteinemia (HHcy) impaired both adhesion and angiogenesis properties of BM-EPCs, accompanied by higher methylation level of CBS promoter that compared to control.
Deficiency in cystathionine beta synthase (CBS) enzyme sometimes leads to hyperhomocysteinemia/homocystinuria, conditions often associated with mental retardation (MR).
In humans, severe hyperhomocysteinemia due to genetic alterations in cystathionine beta-synthase (Cbs) or methylenetetrahydrofolate reductase (Mthfr) results in neurological abnormalities and premature death from vascular complications.
This is the first report from Pakistan where novel as well as recurrent CBS mutations causing hyperhomocysteinemia and lens dislocation in three patients from different families are being reported with the predicted effect of the risk allele of the MTHFR SNP in causing hyperhomocysteinemia.
However, it is not known how much of the observed hyperhomocysteinemia in patients with vascular disease is due to heterozygosity for cystathionine-beta-synthase (CbetaS) deficiency, because a clinically useful screening method is unavailable.
This indicates that a search for CBS mutations in patients with severe hyperhomocysteinemia is important to ensure the detection of a possible CBS deficiency, thus enabling treatment.