title: In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene.
abstract: Trimethylaminuria (TMAU) results from an accumulation of an excessive amount of unoxidized trimethylamine that is excreted in urine and body secretions. Mutations of the flavin-containing monooxygenase 3 (FMO3) gene (a hepatic phase I drug-metabolizing enzyme) account for the severe recessively encoded form of this condition. We have previously described a number of FMO3 polymorphisms which in vitro exhibit reduced substrate affinity for several FMO substrates. Here we show that three prevalent polymorphisms (E158K, V257M, and E308G) inherited in particular combinations confer a slight decrease in TMA oxidation under normal physiological conditions, which may be clinically "silent." With the use of substrate loading or with the interaction of other known modulators of FMO3 activity such as hormonal influences, these genotypes may predispose to mild TMAU.
authors.affiliation: Biochemical Genetics, Montreal Children's Hospital, Montreal, Quebec, Canada.
authors.forename: D M
authors.initials: DM
authors.lastname: Lambert
authors.forename: O A
authors.initials: OA
authors.lastname: Mamer
authors.forename: B R
authors.initials: BR
authors.lastname: Akerman
authors.forename: L
authors.initials: L
authors.lastname: Choinière
authors.forename: D
authors.initials: D
authors.lastname: Gaudet
authors.forename: P
authors.initials: P
authors.lastname: Hamet
authors.forename: E P
authors.initials: EP
authors.lastname: Treacy
mesh_terms: D000483:Alleles; D002170:Canada; D003062:Codon; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008744:Methylamines / Q000378:metabolism / Q000652:urine*; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D010105:Oxygenases / Q000235:genetics; D011110:Polymorphism, Genetic; D011792:Quebec; D012737:Sex Factors
chemical_list: D003062:Codon; D008744:Methylamines; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine; D010100:Oxygen