title: Relationships between flavin-containing mono-oxygenase 3 (FMO3) genotype and trimethylaminuria phenotype in a Japanese population.
abstract: OBJECTIVE
  The aim of this study was to investigate relationships between flavin-containing mono-oxygenase 3 (FMO3) genotype and phenotype (conversion of odorous trimethylamine into non-odorous trimethylamine N-oxide) in a large Japanese cohort suffering from trimethylaminuria.
  
  
  METHODS
  Urinary excretion of trimethylamine and trimethylamine N-oxide was determined for 102 volunteers with self-reporting symptoms of trimethylaminuria. For each we determined the sequence of the entire coding region, plus 1.3 kb of flanking intronic and 2.5 kb of the upstream region of the FMO3 gene. The affect of upstream variants on transcription was determined with a reporter gene assay.
  
  
  RESULTS
  Seventy-eight subjects were diagnosed as suffering from trimethylaminuria, based on urinary excretion of <90% of total TMA as TMA N-oxide. Of these, 13 were classified as severe, 56 as moderate and nine as mild cases, excreting <43%, 48-70% and 73-83% of trimethylamine as trimethylamine N-oxide, respectively. Twenty-seven mutations were identified in FMO3, 15 in the coding region, of which eight abolish or severely impair FMO3 activity (Pro70Leu, Cys197fsX, Thr201Lys, Arg205Cys, Met260Val, Trp388Ter, Gln470Ter and Arg500Ter), and 12 in the upstream region. The mutations segregate into 19 haplotypes, including four different combinations of upstream mutations, each of which reduces transcriptional activity in comparison with the ancestral upstream sequence of FMO3.
  
  
  CONCLUSIONS
  Comparisons of genotype and phenotype reveal that severe trimethylaminuria is caused by loss of function mutations in FMO3. For moderate and mild cases the situation is more complex, with most resulting from factors other than FMO3 genotype. Our results have implications for the diagnosis and management of the disorder.
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Charles K
authors.initials: CK
authors.lastname: Allerston
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Shephard
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Ian R
authors.initials: IR
authors.lastname: Phillips
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008744:Methylamines / Q000652:urine*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D008744:Methylamines; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)
keywords: FMO3; genetic polymorphism; trimethylamine; trimethylamine N-oxide; urine
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