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

Hum Mol Genet. 1998 May;7(5):839-45. doi: 10.1093/hmg/7.5.839.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cloning, Molecular
  • DNA, Complementary / biosynthesis
  • Haplotypes
  • Humans
  • Metabolism, Inborn Errors / genetics*
  • Metabolism, Inborn Errors / urine*
  • Methylamines / urine*
  • Middle Aged
  • Oxygenases / genetics*
  • Oxygenases / physiology*
  • Phenotype
  • Point Mutation / genetics*
  • Recombinant Fusion Proteins / biosynthesis

Substances

  • DNA, Complementary
  • Methylamines
  • Recombinant Fusion Proteins
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • trimethylamine