Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population.
The reduced capacity of flavin-containing monooxygenase 3 (FMO3) to N-oxidize trimethylamine (TMA) is believed to cause a metabolic disorder. The aim of this study was to investigate the inter-individual variations of FMO3. Genomic DNA of case subjects that showed only 10-20% of FMO3 metabolic capacity among self-reported trimethylaminuria Japanese volunteers was sequenced. Functional analysis of recombinant FMO3 proteins was also performed. One homozygote for a novel single nucleotide substitution causing a stop codon at Arg500 was observed. The biological parents of this Proband A were heterozygous and showed >90% TMA N-oxygenation metabolic capacity. Another Proband B had the Arg500Stop and Cys197Stop codons. The TMA N-oxygenation metabolic capacities of the father and brother of this Proband B were apparently observed by possessing Arg205Cys mutant that coded for decreased TMA N-oxygenase. Recombinant Arg500Stop FMO3 cDNA expressed in Escherichia coli membranes and a series of highly purified truncation mutants at different positions of the C-terminus of FMO3 showed no detectable functional activity toward typical FMO3 substrates. The results suggest that individuals homozygous for either of the nonsense mutations, Arg500Stop and/or Cys197Stop alleles, in the FMO3 gene can possess abnormal TMA N-oxygenation.
Yamazaki
Hiroshi
H
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. hyamazak@ac.shoyaku.ac.jp
Fujita
Haruka
H
Gunji
Takaaki
T
Zhang
Jun
J
Kamataki
Tetsuya
T
Cashman
John R
JR
Shimizu
Makiko
M
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics; D008744:Methylamines / Q000378:metabolism / Q000652:urine*; D008875:Middle Aged; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000235:genetics* / Q000502:physiology; D010375:Pedigree
D018389:Codon, Nonsense; D008744:Methylamines; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine