Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome

Nat Genet. 1997 Dec;17(4):491-4. doi: 10.1038/ng1297-491.


Individuals with primary trimethylaminuria exhibit a body odour reminiscent of rotting fish, due to excessive excretion of trimethylamine (TMA; refs 1-3). The disorder, colloquially known as fish-odour syndrome, is inherited recessively as a defect in hepatic N-oxidation of dietary-derived TMA and cannot be considered benign, as sufferers may display a variety of psychosocial reactions, ranging from social isolation of clinical depression and attempted suicide. TMA oxidation is catalyzed by flavin-containing mono-oxygenase (FMO; refs 7,8), and tissue localization and functional studies have established FMO3 as the form most likely to be defective in fish-odour syndrome. Direct sequencing of the coding exons of FMO3 amplified from a patient with fish-odour syndrome identified two missense mutations. Although one of these represented a common polymorphism, the other, a C-->T transition in exon 4, was found only in an affected pedigree, in which it segregated with the disorder. The latter mutation predicts a proline-->leucine substitution at residue 153 and abolishes FMO3 catalytic activity. Our results indicate that defects in FMO3 underlie fish-odour syndrome and that the Pro 153-->Leu 153 mutation described here is a cause of this distressing condition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Humans
  • Metabolism, Inborn Errors / enzymology*
  • Metabolism, Inborn Errors / genetics
  • Methylamines / urine*
  • Molecular Sequence Data
  • Mutation*
  • Odorants*
  • Oxidation-Reduction
  • Oxygenases / genetics*
  • Pedigree
  • Syndrome


  • Methylamines
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • trimethylamine