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Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.

Nackley AG, Shabalina SA, Lambert JE, Conrad MS, Gibson DG, Spiridonov AN, Satterfield SK, Diatchenko L - PLoS ONE (2009)

Bottom Line: Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158)met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions.APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively.These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158)met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs), accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224) is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488) are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity.

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Related in: MedlinePlus

Effect of minor SNPs linked to APS and HPS haplotypes on predicted mRNA secondary structures.Polymorphic alleles C389T, C611G, and G675A that define the three major haplotypes are indicated, minor SNPs underlined, and the major functional RNA stem-loop structure associated with APS and HPS circled. Relative to the APS haplotype, the HPS haplotype coded for a longer, more stable secondary structure. Transcripts carrying the 800A or 641T mutations in the val158 region or the 417T or 422A mutations in the nearby stem-loop did not significantly alter mRNA secondary structure.
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pone-0005237-g001: Effect of minor SNPs linked to APS and HPS haplotypes on predicted mRNA secondary structures.Polymorphic alleles C389T, C611G, and G675A that define the three major haplotypes are indicated, minor SNPs underlined, and the major functional RNA stem-loop structure associated with APS and HPS circled. Relative to the APS haplotype, the HPS haplotype coded for a longer, more stable secondary structure. Transcripts carrying the 800A or 641T mutations in the val158 region or the 417T or 422A mutations in the nearby stem-loop did not significantly alter mRNA secondary structure.

Mentions: To determine whether minor SNPs linked to APS and HPS haplotypes modify mRNA secondary structure, secondary structures were predicted for the APS, APS+800A, HPS, HPS+417T, HPS+422A, and HPS+641T mRNA transcripts using the RNA Mfold [46] and Afold [47] programs. Several structural domains were predicted within the 449 nucleotide region that contained the previously studied val158 SNP as well as the newly studied minor SNPs (Fig. 1). In line with previous studies [37], the HPS haplotype codes for a longer more stable secondary structure in the val158 region relative to the APS haplotype. The 800A and 641T minor alleles located within the structural domain of the val158 region did not significantly alter this local stem-loop structure or nearby structural domains associated with the APS and HPS haplotypes, respectively. The 417T or 422A minor alleles were located outside of the structural domain of the val158 region, within separate stem-loop structures. Inclusion of either 417T or 422A minor alleles in the HPS haplotype did not alter their local stem-loop structure or that of the nearby structural domain of the val158 region. These computer modeling results as well as potential independent effects of minor SNPs carried with the major haplotypes were studied further in in vitro cell transfection experiments.


Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs.

Nackley AG, Shabalina SA, Lambert JE, Conrad MS, Gibson DG, Spiridonov AN, Satterfield SK, Diatchenko L - PLoS ONE (2009)

Effect of minor SNPs linked to APS and HPS haplotypes on predicted mRNA secondary structures.Polymorphic alleles C389T, C611G, and G675A that define the three major haplotypes are indicated, minor SNPs underlined, and the major functional RNA stem-loop structure associated with APS and HPS circled. Relative to the APS haplotype, the HPS haplotype coded for a longer, more stable secondary structure. Transcripts carrying the 800A or 641T mutations in the val158 region or the 417T or 422A mutations in the nearby stem-loop did not significantly alter mRNA secondary structure.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2664927&req=5

pone-0005237-g001: Effect of minor SNPs linked to APS and HPS haplotypes on predicted mRNA secondary structures.Polymorphic alleles C389T, C611G, and G675A that define the three major haplotypes are indicated, minor SNPs underlined, and the major functional RNA stem-loop structure associated with APS and HPS circled. Relative to the APS haplotype, the HPS haplotype coded for a longer, more stable secondary structure. Transcripts carrying the 800A or 641T mutations in the val158 region or the 417T or 422A mutations in the nearby stem-loop did not significantly alter mRNA secondary structure.
Mentions: To determine whether minor SNPs linked to APS and HPS haplotypes modify mRNA secondary structure, secondary structures were predicted for the APS, APS+800A, HPS, HPS+417T, HPS+422A, and HPS+641T mRNA transcripts using the RNA Mfold [46] and Afold [47] programs. Several structural domains were predicted within the 449 nucleotide region that contained the previously studied val158 SNP as well as the newly studied minor SNPs (Fig. 1). In line with previous studies [37], the HPS haplotype codes for a longer more stable secondary structure in the val158 region relative to the APS haplotype. The 800A and 641T minor alleles located within the structural domain of the val158 region did not significantly alter this local stem-loop structure or nearby structural domains associated with the APS and HPS haplotypes, respectively. The 417T or 422A minor alleles were located outside of the structural domain of the val158 region, within separate stem-loop structures. Inclusion of either 417T or 422A minor alleles in the HPS haplotype did not alter their local stem-loop structure or that of the nearby structural domain of the val158 region. These computer modeling results as well as potential independent effects of minor SNPs carried with the major haplotypes were studied further in in vitro cell transfection experiments.

Bottom Line: Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158)met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions.APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively.These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val(158)met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs), accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224) is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488) are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity.

Show MeSH
Related in: MedlinePlus