TY - JOUR
T1 - Serine hydroxymethyltransferase 1 and 2
T2 - Gene sequence variation and functional genomic characterization
AU - Hebbring, Scott J.
AU - Chai, Yubo
AU - Ji, Yuan
AU - Abo, Ryan P.
AU - Jenkins, Gregory D.
AU - Fridley, Brooke
AU - Zhang, Jianping
AU - Eckloff, Bruce W.
AU - Wieben, Eric D.
AU - Weinshilboum, Richard M.
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
KW - Functional genomics
KW - Gene resequencing
KW - Genetic polymorphisms
KW - One carbon metabolism
KW - Serine hydroxymethyltransferase 1 and 2
UR - http://www.scopus.com/inward/record.url?scp=84862804459&partnerID=8YFLogxK
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U2 - 10.1111/j.1471-4159.2012.07646.x
DO - 10.1111/j.1471-4159.2012.07646.x
M3 - Article
C2 - 22220685
AN - SCOPUS:84862804459
SN - 0022-3042
VL - 120
SP - 881
EP - 890
JO - Journal of neurochemistry
JF - Journal of neurochemistry
IS - 6
ER -