Stop codon mutations in the flavin-containing monooxygenase 3 ( FMO3) gene responsible for trimethylaminuria in a Japanese population

• Published in: Molecular genetics and metabolism Vol. 90; no. 1; pp. 58 - 63
• Main Authors: Yamazaki, Hiroshi, Fujita, Haruka, Gunji, Takaaki, Zhang, Jun, Kamataki, Tetsuya, Cashman, John R., Shimizu, Makiko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2007
• Subjects: Adolescent; Adult; Child; Child, Preschool; Codon, Nonsense - genetics; Escherichia coli; Female; Fish-like odor syndrome; Flavin-containing monooxygenase; Humans; Infant; Japan; Japanese; Male; Metabolism, Inborn Errors - enzymology; Metabolism, Inborn Errors - genetics; Methylamines - metabolism; Methylamines - urine; Middle Aged; Oxidation-Reduction; Oxygenases - genetics; Oxygenases - physiology; Pedigree; Trimethylamine; Trimethylaminuria; Truncated FMO3; Japan; Trimethylaminuria; Flavin-containing monooxygenase; Truncated FMO3; Trimethylamine; Fish-like odor syndrome; Japanese
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2006.08.008

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.