Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome.
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.
Dolphin
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Department of Biochemistry, Queen Mary & Westfield College, University of London, UK.
Janmohamed
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Smith
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Shephard
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Phillips
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics; D008744:Methylamines / Q000652:urine*; D008969:Molecular Sequence Data; D009154:Mutation; D009812:Odorants; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome
D008744:Methylamines; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine