Ep. Treacy et al., MUTATIONS OF THE FLAVIN-CONTAINING MONOOXYGENASE GENE (FMO3) CAUSE TRIMETHYLAMINURIA, A DEFECT IN DETOXICATION, Human molecular genetics, 7(5), 1998, pp. 839-845
Individuals with the recessive condition trimethylaminuria exhibit var
iation in metabolic detoxication of xenobiotics by hepatic flavin-cont
aining monooxygenases. We show here that mutations in the human flavin
-containing monooxygenase isoform 3 gene (FMO3) impair N-oxygenation o
f 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. Nonse
nse and missense mutations are associated with a severe phenotype and
are also implicated in impaired metabolism of other nitrogen-and sulfu
r-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 met
abolism of xenobiotic substrates and endogenous amines.