Sequence variations in the flavin‐containing mono‐oxygenase 3 gene (FMO3) in fish odour syndrome

Trimethylaminuria is inherited recessively as a defect in hepatic N ‐oxidation of dietary derived trimethylamine (TMA) which causes excess excretion of TMA so that affected individuals have a body odour resembling rotten fish. Flavin‐containing mono‐oxygenase 3 (FMO3) catalyses TMA oxidation and mutations in the FMO3 gene have recently been shown to underlie trimethylaminuria/fish odour syndrome. We searched for FMO3 mutations in a previously unreported individual with this disorder using polymerase chain reaction of genomic DNA, heteroduplex analysis and direct sequencing of heteroduplex band shifts. We identified a heterozygous missense Pro153→Leu153 mutation in exon 4. Leu153 has been reported previously as a homozygous mutation in two unrelated siblings with trimethylaminuria and has been shown to result in total loss of FMO3 enzyme activity. In our patient, two further missense mutations were identified on the other FMO3 allele, Val143→Glu143 and Glu158→Lys158. Lys158 is known to be a common polymorphism, but has functional significance in reducing enzyme activity by 10%. Glu143 has not been documented previously, but was shown to be a rare polymorphism and may be of further relevance in reducing FMO3 activity. Mutagenesis studies and enzyme assays will be necessary to confirm or refute the potential pathogenic significance of Glu143 in this patient, but the mutation Pro153→Leu153 appears to be a recurrent cause of this distressing metabolic disorder.