| 5130171 | Phenylethanolamine N-methyltransferase (PNMT) gene and early-onset Alzheimer disease. | Mann MB, etal., Am J Med Genet. 2001 May 8;105(4):312-6. | The activity of human phenylethanolamine N-methyltransferase (PNMT) is reduced in the neurons of those cells in many subcortical areas of the brain that are known to undergo neurodegeneration in Alzheimer disease (AD). Others have reported that PNMT -weight:700;'>PNMT is decreased in brains of persons with AD and that the decrease in enzymatic activity is due to a reduced amount of the enzyme protein. We have previously described two polymorphisms, G-353A and G-148A, in the promoter region of the gene coding for PNMT. These markers were tested for their association with the occurrence of sporadic AD. Genotyping of 131 necropsy confirmed AD cases, and 947 adult nondemented controls were completed. We observed a significant association between both of the PNMT gene polymorphisms and early-onset AD (EOAD) (P < or = 0.007), but not in late-onset AD (LOAD). These data suggest that genetic variation in the promoter of the PNMT gene is associated with increased susceptibility to the sporadic form of EOAD. | 11378842 | 2001-04-01 |
| 5130164 | Association of polymorphisms in the promoter region of the PNMT gene with essential hypertension in African Americans but not in whites. | Cui J, etal., Am J Hypertens. 2003 Oct;16(10):859-63. | BACKGROUND: Several studies have indicated that a region on human chromosome 17 may influence blood pressure. Our group reported positive linkage for hypertension to the region on human chromosome 17, between D17S1814 and D17S800 in white sibling pairs. In this study, we further investigated this re sult by examining the phenylethanolamine N-methyltransferase (PNMT) gene, which is located at 17q21 within the region where we found linkage. METHODS: A case/control association study was conducted to evaluate the relationship between genetic variants of the PNMT gene and risk for essential hypertension. Two single nucleotide polymorphisms (SNPs) in the promoter region of the gene were genotyped, PNMT-148 and PNMT-353, in three ethnic samples: African American (117 hypertensive, 96 normotensive), American white (91 hypertensive, 80 normotensive), and Greek white (99 hypertensive, 90 normotensive), using the homogeneous mass extend reaction (Sequenom) and RFLP for genotyping. RESULTS: A significant difference in allelic frequency of SNP-353 between hypertensives (38.02%) and normotensives (27.35%) in African Americans (P =.019) was found; however, no significant differences were observed for this SNP for the other ethnic groups. No association was found with SNP PNMT-148 in any of the ethnic groups. Frequencies of haplotypes based on the two SNPs were also compared between hypertensive and normotensive individuals. No significant difference was found in estimated haplotype frequencies between hypertensive and control subjects in the three ethnic groups. CONCLUSIONS: These results suggest that genetic variants of PNMT may play a role in the development of essential hypertension. | 14553966 | 2003-04-01 |
| 329853327 | Conserved regulatory motifs at phenylethanolamine N-methyltransferase (PNMT) are disrupted by common functional genetic variation: an integrated computational/experimental approach. | RodrÃguez-Flores JL, etal., Mamm Genome. 2010 Apr;21(3-4):195-204. doi: 10.1007/s00335-010-9253-y. Epub 2010 Mar 5. | The adrenomedullary hormone epinephrine transduces environmental stressors into cardiovascular events (tachycardia and hypertension). Although the epinephrine biosynthetic enzyme PNMT genetic locus displays both linkage and association to such traits, genetic va riation underlying these quantitative phenotypes is not established. Using an integrated suite of computational and experimental approaches, we elucidate a functional mechanism for common (minor allele frequencies > 30%) genetic variants at PNMT. Transcription factor binding motif prediction on mammalian PNMT promoter alignments identified two variant regulatory motifs, SP1 and EGR1, disrupted by G-367A (rs3764351), and SOX17 motif created by G-161A (rs876493). Electrophoretic mobility shifts of approximately 30-bp oligonucleotides containing ancestral versus variant alleles validated the computational hypothesis. Queried against chromaffin cell nuclear protein extracts, only the G-367 and -161A alleles shifted. Specific antibodies applied in electrophoretic gel shift experiments confirmed binding of SP1 and EGR1 to G-367 and SOX17 to -161A. The in vitro allele-specific binding was verified in cella through promoter reporter assays: lower activity for -367A haplotypes cotransfected by SP1 (p = 0.002) and EGR1 (p = 0.034); and enhanced inhibition of -161A haplotypes (p = 0.0003) cotransfected with SP1 + SOX17. Finally, we probed cis/trans regulation with endogenous factors by chromatin immunoprecipitation using SP1/EGR1/SOX17 antibodies. We describe the systematic application of complementary computational and experimental techniques to detect and document functional genetic variation in a trait-associated regulatory region. The results provide insight into cis and trans transcriptional mechanisms whereby common variation at PNMT can give rise to quantitative changes in human physiological and disease traits. Thus, PNMT variants in cis may interact with nuclear factors in trans to govern adrenergic activity. | 20204374 | 2010-04-01 |
| 628457 | Existence of cardiac PNMT mRNA in adult rats: elevation by stress in a glucocorticoid-dependent manner. | Krizanova O, etal., Am J Physiol Heart Circ Physiol 2001 Sep;281(3):H1372-9. | Phenylethanolamine N-methyltransferase (PNMT) is the enzyme that synthesizes epinephrine from norepinephrine. The aim of this study was to determine potential PNMT gene expression in the cardiac atria and ventricles of adult rats and to examine whether the gene expression of this enzyme is affected by immobilization stress. PNMT mRNA levels were detected in all four parts of the heart, with the highest level in the left atrium. Both Southern blot and sequencing verified the specificity of PNMT detected by RT-PCR. Single immobilization for 2 h increased gene expression of PNMT in both atria and ventricles. In atria, this effect was clearly modulated by glucocorticoids, because either adrenalectomy or hypophysectomy prevented the increase in PNMT mRNA levels in response to immobilization stimulus. This study establishes, for the first time, that PNMT gene expression occurs in cardiac atria and also, to a small extent, in ventricles of adult rats. Immobilization stress increases gene expression in atria and ventricles. This increase requires an intact hypothalamus-pituitary-adrenocortical axis, indicating the involvement of glucocorticoids. | 11514309 | 2001-01-01 |
| 1601428 | Modulation by 6-hydroxydopamine of expression of the phenylethanolamine N-methyltransferase (PNMT) gene in the rat heart during immobilization stress. | Tillinger A, etal., Stress. 2006 Dec;9(4):207-13. | Phenylethanolamine N-methyltransferase (PNMT) is the final enzyme in the catecholamine synthesizing cascade that converts noradrenaline (NA) to adrenaline (Adr). Both of these catecholamines are physiologically important hormones and neurotransmitters in mammals with profound influence on the activity of the cardiovascular system. Although PNMT activity and gene expression have been reported in the neonatal and also adult rat heart, little is known about the identity of the cells expressing PNMT mRNA. In this study, we have shown that besides PNMT in neuronal and intrinsic cardiac cells, this enzyme is expressed also in rat cardiomyocytes, as shown by immunofluorescence in isolated cardiomyocytes.To determine which cells in the heart more sensitively show stress-induced changes in PNMT mRNA expression, we performed chemical sympathectomy by administration of 6-hydroxydopamine (6-OHDA), which destroys catecholaminergic terminals. We determined PNMT mRNA levels in the left atria and ventricles of control and stressed rats. In the rats treated with 6-OHDA, PNMT mRNA levels were not changed under normal, physiological conditions compared to vehicle treated rats. Similar results were observed on isolated cardiomyocytes from control and 6-OHDA treated rats. However, 6-OHDA treatment prevented immobilization-induced increase in PNMT mRNA expression. The results allow us to propose that in the heart, the immobilization-induced increase in PNMT gene expression is probably not in cardiomyocytes, but in neuronal cells. | 17175506 | 2006-04-01 |
| 5130172 | Resequencing PNMT in European hypertensive and normotensive individuals: no common susceptibilily variants for hypertension and purifying selection on intron 1. | Kepp K, etal., BMC Med Genet. 2007 Jul 23;8:47. | BACKGROUND: Human linkage and animal QTL studies have indicated the contribution of genes on Chr17 into blood pressure regulation. One candidate gene is PNMT, coding for phenylethanolamine-N-methyltransferase, catalyzing the synthesis of epinephrine from norepin ephrine. METHODS: Fine-scale variation of PNMT was screened by resequencing hypertensive (n = 50) and normotensive (n = 50) individuals from two European populations (Estonians and Czechs). The resulting polymorphism data were analyzed by statistical genetics methods using Genepop 3.4, PHASE 2.1 and DnaSP 4.0 software programs. In silico prediction of transcription factor binding sites for intron 1 was performed with MatInspector 2.2 software. RESULTS: PNMT was characterized by minimum variation and excess of rare SNPs in both normo- and hypertensive individuals. None of the SNPs showed significant differences in allelic frequencies among population samples, as well as between screened hypertensives and normotensives. In the joint case-control analysis of the Estonian and the Czech samples, hypertension patients had a significant excess of heterozygotes for two promoter region polymorphisms (SNP-184; SNP-390). The identified variation pattern of PNMT reflects the effect of purifying selection consistent with an important role of PNMT-synthesized epinephrine in the regulation of cardiovascular and metabolic functions, and as a CNS neurotransmitter. A striking feature is the lack of intronic variation. In silico analysis of PNMT intron 1 confirmed the presence of a human-specific putative Glucocorticoid Responsive Element (GRE), inserted by Alu-mediated transfer. Further analysis of intron 1 supported the possible existence of a full Glucocorticoid Responsive Unit (GRU) predicted to consist of multiple gene regulatory elements known to cooperate with GRE in driving transcription. The role of these elements in regulating PNMT expression patterns and thus determining the dynamics of the synthesis of epinephrine is still to be studied. CONCLUSION: We suggest that the differences in PNMT expression between normotensives and hypertensives are not determined by the polymorphisms in this gene, but rather by the interplay of gene expression regulators, which may vary among individuals. Understanding the determinants of PNMT expression may assist in developing PNMT inhibitors as potential novel therapeutics. | 17645789 | 1000-04-01 |
