title: Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication.
abstract: Individuals with the recessive condition trimethylaminuria exhibit variation in metabolic detoxication of xenobiotics by hepatic flavin-containing monooxygenases. We show here that mutations in the human flavin-containing monooxygenase isoform 3 gene ( FMO3 ) impair N -oxygenation of xenobiotics and are responsible for the trimethylaminuria phenotype. Three disease-causing mutations in nine Australian-born probands have been identified which share a particular polymorphic haplotype. Nonsense and missense mutations are associated with a severe phenotype and are also implicated in impaired metabolism of other nitrogen- and sulfur-containing substrates including biogenic amines, both clinically and when mutated proteins expressed from cDNA are studied in vitro . These findings illustrate the critical role played by human FMO3 in the metabolism of xenobiotic substrates and endogenous amines.
authors.affiliation: McGill University, Montreal Children's Hospital Research Institute, Montreal, Quebec H3H 1P3, Canada. mcet@musica.mcgill.ca
authors.forename: E P
authors.initials: EP
authors.lastname: Treacy
authors.forename: B R
authors.initials: BR
authors.lastname: Akerman
authors.forename: L M
authors.initials: LM
authors.lastname: Chow
authors.forename: R
authors.initials: R
authors.lastname: Youil
authors.forename: C
authors.initials: C
authors.lastname: Bibeau
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.forename: A G
authors.initials: AG
authors.lastname: Bruce
authors.forename: M
authors.initials: M
authors.lastname: Knight
authors.forename: D M
authors.initials: DM
authors.lastname: Danks
authors.forename: J R
authors.initials: JR
authors.lastname: Cashman
authors.forename: S M
authors.initials: SM
authors.lastname: Forrest
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000096:biosynthesis; D006239:Haplotypes; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000652:urine*; D008744:Methylamines / Q000652:urine*; D008875:Middle Aged; D010105:Oxygenases / Q000235:genetics* / Q000502:physiology*; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis
chemical_list: D018076:DNA, Complementary; D008744:Methylamines; D011993:Recombinant Fusion Proteins; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine