Genetic polymorphism of the flavin-containing monooxygenase 3 (FMO3) associated with trimethylaminuria (fish odor syndrome): observations from Japanese patients.
Trimethylaminuria (fish odor syndrome) is a metabolic disorder characterized by the inability to convert malodorous dietary-derived trimethylamine (TMA) to odorless TMA N-oxide by the flavin-containing monooxygenase 3 (FMO3). Mutations of the FMO3 gene were investigated in Japanese trimethylaminuria that showed low FMO3 metabolic capacity. Novel polymorphisms in the FMO3 gene causing stop codons at Cys197, Trp388, Gln470 or Arg500 of FMO3 were discovered in self-reported trimethylaminuria Japanese volunteers. Different metabolic capacities of FMO3 were observed for Asn114Ser, Thr201Lys, Arg205Cys or Met260Val FMO3 variants in addition to common Glu158Lys, Val257Met, and Glu308Gly FMO3. Estimated allelic frequencies for these novel mutated FMO3 genes for the Japanese population examined was approximately 1-4 % in this Japanese cohort. Recombinant Arg500stop (94% of the whole FMO3 structure) and several missense FMO3 variants showed no detectable activity and different effects on N- and S-oxygenation activities, respectively. The family members of Japanese probands who were heterozygous for these nonsense mutants generally showed moderate TMA N-oxygenation metabolic capacity, suggesting that heterozygotes for the nonsense mutations will exhibit trimethylaminuria symptoms only if they have, on the other chromosome, a mutation that substantially impairs enzyme activity. In addition, other causal factors for decreased FMO3 metabolic capacity such as liver damage or menstruation and treatment with copper chlorophyllin are also included in this minireview. The present article provides fundamental information for the importance of future investigations of the human FMO3 gene associated with trimethylaminuria (fish odor syndrome).
Yamazaki
Hiroshi
H
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. hyamazak@ac.shoyaku.ac.jp
Shimizu
Makiko
M
D000483:Alleles; D044466:Asian People / Q000235:genetics*; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008744:Methylamines / Q000378:metabolism; D009154:Mutation; D010105:Oxygenases / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic
D008744:Methylamines; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine