Genetic variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects identified by phenotyping for trimethylaminuria and found in a database of genome resources

• Published in: Drug metabolism and pharmacokinetics Vol. 38; p. 100387
• Main Authors: Shimizu, Makiko, Koibuchi, Natsumi, Mizugaki, Ami, Hishinuma, Eiji, Saito, Sakae, Hiratsuka, Masahiro, Yamazaki, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2021
• Subjects: Fish odor syndrome; FMO3; Haplotype; Mega database; Trimethylamine N-Oxide; Fish odor syndrome; Trimethylamine N-Oxide; FMO3; Mega database; Haplotype
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2021.100387

The oxygenation of food-derived trimethylamine to its N-oxide is a representative reaction mediated by human flavin-containing monooxygenase 3 (FMO3). Impaired FMO3 enzymatic activity is associated with trimethylaminuria (accumulation of substrate), whereas trimethylamine N-oxide (metabolite) is associated with arteriosclerosis. We previously reported FMO3 single-nucleotide and/or haplotype variants with low FMO3 metabolic capacity using urinary phenotyping and the whole-genome sequencing of Japanese populations. Here, we further analyze Japanese volunteers with self-reported malodor and interrogate an updated Japanese database for novel FMO3 single-nucleotide and/or haplotype variants. After 3 years of follow up, seven probands were found to harbor the known impaired FMO3 variant p.(Gly191Cys) identified in the database or novel variants/haplotypes including p.(Met66Val), p.(Arg223Gln), p.(Glu158Lys;Glu308Gly;Arg492Trp), and p.(Glu158Lys;Glu308Gly;Pro496Ser). The known severe mutation p.(Cys197Ter) (a TG deletion) and four variants including p.(Tyr269His) and p.(Pro496Ser) were first detected in the updated genome panel. Among previously unanalyzed FMO3 variants, the trimethylamine/benzydamine N-oxygenation activities of recombinant p.(Met66Val), p.(Arg223Gln), p.(Tyr269His), p.(Glu158Lys;Glu308Gly;Arg492Trp), and p.(Glu158Lys;Glu308Gly;Pro496Ser) FMO3 variant proteins were severely decreased (Vmax/Km <10% of wild-type). Although the present novel mutations or alleles were relatively rare, both in self-reported Japanese trimethylaminuria sufferers and in the genomic database panel, three common FMO3 missense or deletion variants severely impaired FMO3-mediated N-oxygenation of trimethylamine. [Display omitted]