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Human phenylethanolamine N‐methyltransferase (PNMT) pharmacogenetics: gene resequencing and functional genomic studies
Author(s) -
Ji Y.,
Salavaggione O. E.,
Adjei A. A.,
Thomae B. A.,
Eckloff B.,
Wieben E. D.,
Weinshilboum R. M.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.361
Subject(s) - nonsynonymous substitution , biology , exon , microbiology and biotechnology , gene , genetics , genomic dna , single nucleotide polymorphism , methyltransferase , pharmacogenetics , phenylethanolamine , intron , phenylethanolamine n methyltransferase , methylation , biochemistry , enzyme , genotype , genome , tyrosine hydroxylase
PNMT (EC 2.1.1.28) catalyzes the N‐methylation of norepinephrine to form epinephrine. We set out to resequence the human PNMT gene, including all exons and introns as well as approximately 1 kb of the 5′‐flanking region using Coriell Institute DNA samples from 60 African‐American (AA) and 60 Caucasian‐American (CA) subjects. Within the 3.5 kb resequenced, 17 single nucleotide polymorphisms (SNPs) were observed, including 3 nonsynonymous cSNPs (Asn9Ser, Thr98Ala and Arg112Cys). When constructs for the nonsynonymous cSNPs were transiently expressed in COS‐1 cells, the Ala98 allozyme displayed virtually no enzyme activity or immunoreactive protein when compared with the wild type (WT) allozyme (P<0.01), while values for the other variant allozymes did not differ significantly from those for WT. Rabbit reticulocyte lysate studies showed that the decrease in immunoreactive protein for the Ala98 allozyme was due–at least in part–to accelerated protein degradation. These observations raise the possibility of inherited variation in the ability to form epinephrine from norepinephrine. Clinical Pharmacology & Therapeutics (2004) 75 , P95–P95; doi: 10.1016/j.clpt.2003.11.361