Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication

Individuals with the recessive condition trimethylaminuria exhibitvariation in metabolic detoxication of xenobiotics by hepatic flavin-containing monooxygenases. We show here that mutations in the humanflavin-containing monooxygenase isoform 3 gene ( FMO3 ) impair N -oxygenation of xenobiotics and are responsible for the trimethylaminuriaphenotype. Three disease-causing mutations in nine Australian-born probandshave been identified which share a particular polymorphic haplotype.Nonsense and missense mutations are associated with a severe phenotype andare also implicated in impaired metabolism of other nitrogen- andsulfur-containing substrates including biogenic amines, both clinically andwhen mutated proteins expressed from cDNA are studied in vitro . Thesefindings illustrate the critical role played by human FMO3 in themetabolism of xenobiotic substrates and endogenous amines.