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Received for publication April 30, 2003.
Revised May 22, 2003.
Accepted for publication June 6, 2003.
The flavin-containing monooxygenases (FMOs) are important for the disposition of a variety of toxicants, therapeutics, and dietary components. Although FMO1 is the dominant isoform in fetal liver and adult kidney and intestine and despite up to a 10-fold inter-subject variation in expression, a paucity of information is available on FMO1 genetic variability. To address this issue, 24 samples from the Coriell DNA Polymorphism Discovery Resource Panel were sequenced revealing ten common single nucleotide polymorphisms (SNPs): four located upstream of the structural gene; three within exonic sequences; one within the intron 1 splice donor site; and two with the 3'-untranslated region. Six of these variants are novel. Compared to other FMO loci within the chromosome 1q23-25 cluster, FMO1 appears more highly conserved. Of the identified FMO1 SNPs, only a C>A transversion 9,536 bp upstream of the exon 2 ATG start codon (g.-9,536C>A) would likely affect function, as it lies within the conserved core binding sequence for the yin yang 1 (YY1) transcription factor. Electrophoretic mobility shift assays demonstrated that the g.-9,536C>A transversion eliminated YY1 binding. Further, data from transient expression assays in HepG2 cells suggested this SNP could account for a 2- to 3-fold loss of FMO1 promoter activity. Genotype analysis revealed a g.-9,536A allele (FMO1*6) frequency of 13 and 11% in African- and northern European-Americans, respectively, but a significantly higher frequency of 30% in Hispanic-Americans. Thus, the FMO1*6 variant may account for some of the observed interindividual variation in FMO1 expression.
Key words:
FMO1, flavin-containing monooxygenase (FMO), gene regulation, genetic variability, regulatory polymorphism, yin yang 1
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