Serine hydroxymethyltransferase 1 and 2: Gene sequence variation and functional genomic characterization

Scott J. Hebbring, Yubo Chai, Yuan Ji, Ryan P. Abo, Gregory D. Jenkins, Brooke Fridley, Jianping Zhang, Bruce W. Eckloff, Eric D. Wieben, Richard M. Weinshilboum

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Serine hydroxymethyltransferase (SHMT) catalyzes the transfer of a β-carbon from serine to tetrahydrofolate to form glycine and 5,10-methylene-tetrahydrofolate. This reaction plays an important role in neurotransmitter synthesis and metabolism. We set out to resequence SHMT1 and SHMT2, followed by functional genomic studies. We identified 87 and 60 polymorphisms in SHMT1 and SHMT2, respectively. We observed no significant functional effect of the 13 nonsynonymous single-nucleotide polymorphism (SNPs) in these genes, either on catalytic activity or protein quantity. We imputed additional variants across the two genes using '1000 Genomes' data, and identified 14 variants that were significantly associated (p < 1.0E-10) with SHMT1 messenger RNA expression in lymphoblastoid cell lines. Many of these SNPs were also significantly correlated with basal SHMT1 protein expression in 268 human liver biopsy samples. Reporter gene assays suggested that the SHMT1 promoter SNP, rs669340, contributed to this variation. Finally, SHMT1 and SHMT2 expression were significantly correlated with those of other Folate and Methionine Cycle genes at both the messenger RNA and protein levels. These experiments represent a comprehensive study of SHMT1 and SHMT2 gene sequence variation and its functional implications. In addition, we obtained preliminary indications that these genes may be co-regulated with other Folate and Methionine Cycle genes.

Original languageEnglish (US)
Pages (from-to)881-890
Number of pages10
JournalJournal of neurochemistry
Issue number6
StatePublished - Mar 2012


  • Functional genomics
  • Gene resequencing
  • Genetic polymorphisms
  • One carbon metabolism
  • Serine hydroxymethyltransferase 1 and 2

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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