Splicing variants of the porcine betaine-homocysteine S-methyltransferase gene: Implications for mammalian metabolism

- Expression of ten bhmt splice variants (9 novel) varied across tissues and age.
- Two variants contained an ORF that encoded a truncated form of BHMT (tBHMT).
- Wild type BHMT is an (βα)8 barrel but tBHMT is predicted to assume a horseshoe fold.
- tBHMT, if translated, would lack methyltransferase activity.
- bhmt promoter methylation has a role in expression.

Betaine-homocysteine S-methyltransferase (BHMT) activity is only detected in the liver of rodents, but in both the liver and kidney cortex of humans and pigs; therefore, the pig was chosen as a model to define the spatial and temporal expression of BHMT during development. During fetal development, a total of ten splice variants of bhmt were expressed at varying levels across a wide range of porcine tissues. Two variants contained an identical ORF that encoded a C-terminal truncated form of BHMT (tBHMT). The bhmt transcripts were expressed at significant levels in the liver and kidney from day 45 of gestation (G45) onward. The transcripts encoding tBHMT represented 5-13% of the total bhmt transcripts in G30 fetus, G45 liver, and adult liver and kidney cortex. The dominant structural feature of wild type BHMT is an (βα)8 barrel, however, a modeled structure of tBHMT suggests that this protein would assume a horseshoe fold and lack methyltransferase activity. Low BHMT activity was detected in the G30 fetus, and slightly increased levels of activity were observed in the liver from G45 and G90 fetuses. The bhmt promoter contained three key CpG sites, and methylation of these sites was significantly higher in adult lung compared to adult liver. The data reported herein suggest that genomic DNA methylation and variation of the 5′ and 3′ UTRs of bhmt transcripts are key regulators for the level of BHMT transcription and translation.