Rare but impaired flavin-containing monooxygenase 3 (FMO3) variants reported in a recently updated Japanese mega-databank of genome resources

• Published in: Drug metabolism and pharmacokinetics Vol. 55; p. 100539
• Main Authors: Shimizu, Makiko, Makiguchi, Miaki, Hishinuma, Eiji, Saito, Sakae, Hiratsuka, Masahiro, Yamazaki, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2024
• Subjects: FMO; Tohoku medical mega bank; Trimethylamine; FMO; Tohoku medical mega bank; Trimethylamine
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2023.100539

Genetic variants of human flavin-containing monooxygenase 3 (FMO3) were investigated using an updated Japanese population panel containing 54,000 subjects (the previous panel contained 38,000 subjects). One stop codon mutation and six amino acid-substituted FMO3 variants were newly identified in the updated databank. Of these, two substituted variants (p.Thr329Ala and p.Arg492Trp) were previously identified in compound haplotypes with p.[(Glu158Lys; Glu308Gly)] and were associated with the metabolic disorder trimethylaminuria. Three recombinant FMO3 protein variants (p.Ser137Leu, p.Ala334Val, and p.Ile426Val) expressed in bacterial membranes had similar activities toward trimethylamine N-oxygenation (∼75–125 %) as wild-type FMO3 (117 min−1); however, the recombinant novel FMO3 variant Phe313Ile showed moderately decreased FMO3 catalytic activity (∼20 % of wild-type). Because of the known deleterious effects of FMO3 C-terminal stop codons, the novel truncated FMO3 Gly184Ter variant was suspected to be inactive. To easily identify the four impaired FMO3 variants (one stop codon mutation and three amino-acid substitutions) in the clinical setting, simple confirmation methods for these FMO3 variants are proposed using polymerase chain reaction/restriction fragment length polymorphism or allele-specific PCR methods. The updated whole-genome sequence data and kinetic analyses revealed that four of the seven single-nucleotide nonsense or missense FMO3 variants had moderately or severely impaired activity toward trimethylamine N-oxygenation. [Display omitted]