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

C T Dolphin, A Janmohamed, R L Smith, E A Shephard, I R Phillips, Colin Dolphin

Research output: Contribution to journalArticlepeer-review

232 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)491-4
Number of pages4
JournalNature Genetics
Volume17
Issue number4
DOIs
Publication statusPublished - Dec 1997

Keywords

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Humans
  • Metabolism, Inborn Errors
  • Methylamines
  • Molecular Sequence Data
  • Mutation
  • Odors
  • Oxidation-Reduction
  • Oxygenases
  • Pedigree
  • Syndrome

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