Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication.
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.
Treacy
E P
EP
McGill University, Montreal Children's Hospital Research Institute, Montreal, Quebec H3H 1P3, Canada. mcet@musica.mcgill.ca
Akerman
B R
BR
Chow
L M
LM
Youil
R
R
Bibeau
C
C
Lin
J
J
Bruce
A G
AG
Knight
M
M
Danks
D M
DM
Cashman
J R
JR
Forrest
S M
SM
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
D018076:DNA, Complementary; D008744:Methylamines; D011993:Recombinant Fusion Proteins; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine