Betaine-Homocysteine Methyltransferase (BHMT): Genomic Sequencing and Relevance to Hyperhomocysteinemia and Vascular Disease in Humans

Heil, Sandra G.; Lievers, Karin J.A; Boers, G.H.J.; Verhoef, Petra; Heijer, Martin den; Trijbels, Frans J.M.; Blom, Henk J.

doi:10.1006/mgme.2000.3078

Cited by 63 publications

(51 citation statements)

References 23 publications

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“…In BHMT, 25 SNPs were observed, including 4 nonsynonymous SNPs that resulted in the following changes in encoded amino acids: Arg(16)Cys, Pro(197) Ser, Gly(199)Ser, and Arg(239)Gln. The Gly(199)Ser and Arg(239)Gln variants have been reported previously [35] and do not appear to influence circulating homocysteine levels [36] -observations compatible with our functional genomic results (Fig. 3A and Fig.…”

Section: Discussionsupporting

confidence: 92%

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Feng

Lee

et al. 2008

Molecular Genetics and Metabolism

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Betaine-homocysteine methyltransferase (BHMT) catalyzes the remethylation of homocysteine. BHMT2 encodes a protein 73% identical in amino acid sequence to BHMT, but the function of BHMT2 remains unclear. We set out to identify and functionally characterize common genetic variation in BHMT and BHMT2. Specifically, we sequenced exons, exon-intron splice junctions and the 5′-flanking regions (5′-FRs) of BHMT and BHMT2 using 240 DNA samples from four ethnic groups. Twenty-five single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs, and 39 SNPs, including 4 nonsynonymous, were observed in BHMT and BHMT2, respectively. BHMT wild type (WT) and variant allozymes were expressed in COS-1 cells. Variant allozymes showed no significant differences from WT in levels of enzyme activity or immunoreactive protein, but there were statistically significant differences in apparent K m values. Luciferase reporter gene constructs were created for the three most common BHMT 5′-FR haplotypes, and significant variation was observed in the ability of these constructs to drive transcription. Although BHMT2 mRNA has been observed in human liver and kidney, expression of the protein has not been reported. We were unable to express BHMT2 in mammalian cells, and the protein aggregated after bacterial expression. Furthermore, BHMT2 was rapidly degraded in a rabbit reticulocyte lysate, but it could be stabilized by cotransfection of COS-1 cells with BHMT and, after cotransfection, it coprecipitated with BHMT. These studies have defined common genetic variation in BHMT and BHMT2 and functionally characterized BHMT SNPs. They may also help to explain why BHMT2 has not previously been defined functionally.

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Section: Discussionsupporting

confidence: 92%

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Feng

Lee

et al. 2008

Molecular Genetics and Metabolism

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“…Both BHMT and MTRR are involved in maintaining cellular levels of methionine; BHMT catalyzes the re-methylation of homocysteine to methionine, predominantly in the liver and kidney (49), whereas MTRR activates MTR, which also catalyzes the re-methylation of homocysteine to methionine in various tissues. (50,51) and spina bifida (52) associated with Gln/Gln versus Arg/Arg at BHMT codon 239 have been suggested among three previous studies. However, another study observed no association with spina bifida (53), and Arg 239 Gln has not been associated with altered BHMT activity (51) or homocysteine levels (50).…”

Section: Resultsmentioning

confidence: 87%

“…(50,51) and spina bifida (52) associated with Gln/Gln versus Arg/Arg at BHMT codon 239 have been suggested among three previous studies. However, another study observed no association with spina bifida (53), and Arg 239 Gln has not been associated with altered BHMT activity (51) or homocysteine levels (50). Although the evidence for an association between BHMT Arg 239 Gln and homocysteine-related diseases is weak, the suggested reduced risks of cardiovascular disease and spina bifida is in contrast to the increased risk of colorectal cancer due to the Gln allele that we observed.…”

Section: Resultsmentioning

confidence: 87%

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

Koushik

Kraft

Fuchs

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The Ala 222 Val single nucleotide polymorphism (SNP) in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in one-carbon metabolism, has been associated with colorectal cancer risk. Many enzymes are involved in one-carbon metabolism, and SNPs in the corresponding genes may play a role in colorectal carcinogenesis. We examined 24 nonsynonymous SNPs in 13 genes involved in the one-carbon metabolism pathway in relation to the risk of colorectal cancer in a case-control study nested in the

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“…There is only one study that reported polymorphisms in the BHMT gene and the in£uence of three BHMT variants on homocysteine concentrations and CVD risk. 85 We found one variant, the 1218G!T (Q406H) substitution, in only one patient and one control in the heterozygous state. The other two variants, the 595G!A (G199S) and the 716G!A (Q239R) transitions, were found to be more frequent but showed no associations with homocysteine concentrations and were not associated with an increased CVD risk.…”

Section: Betaine-homocysteine Methyl Transferasementioning

confidence: 83%

Genetics of hyperhomocysteinaemia in cardiovascular disease

2003

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Homocysteine, a sulphur amino acid, is a branch-point intermediate of methionine metabolism. It can be degraded in the transsulphuration pathway to cystathionine, or remethylated to methionine via the remethylation pathway. In both pathways, major genetic defects that cause enzyme de ciencies are associated with very high plasma homocysteine concentrations and excretion of homocystine into the urine. Mildly elevated plasma homocysteine concentrations are thought to be an independent and graded risk factor for both arterial occlusive disease and venous thrombosis. Genetic defects in genes encoding enzymes involved in homocysteine metabolism, or depletion of important cofactors or (co)substrates for those enzymes, including folate, vitamin B 12 and vitamin B 6 , may result in elevated plasma homocysteine concentrations. Plasma homocysteine concentrations are also in uenced by dietary and lifestyle factors. In the last decade, several studies have been conducted to elucidate the genetic determinants of hyperhomocysteinaemia in patients with cardiovascular disease. We report on both environmental and genetic determinants of hyperhomocysteinaemia and give a detailed overview of all the genetic determinants that have been reported to date.

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Betaine-Homocysteine Methyltransferase (BHMT): Genomic Sequencing and Relevance to Hyperhomocysteinemia and Vascular Disease in Humans

Cited by 63 publications

References 23 publications

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

Genetics of hyperhomocysteinaemia in cardiovascular disease

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