Genetic variants of flavin-containing monooxygenase 3 (FMO3) derived from Japanese subjects with the trimethylaminuria phenotype and whole-genome sequence data from a large Japanese database

• Published in: Drug metabolism and pharmacokinetics Vol. 34; no. 5; pp. 334 - 339
• Main Authors: Shimizu, Makiko, Yoda, Hiromi, Nakakuki, Komei, Saso, Aoi, Saito, Iria, Hishinuma, Eiji, Saito, Sakae, Hiratsuka, Masahiro, Yamazaki, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2019
• Subjects: Child, Preschool; Databases, Genetic; Female; Fish-like odor syndrome; FMO3; Frameshift; Genetic Variation - genetics; Humans; Japan; Large database; Male; Metabolism, Inborn Errors - genetics; Metabolism, Inborn Errors - metabolism; Methylamines - metabolism; Methylamines - urine; Middle Aged; Oxygenases - genetics; Oxygenases - metabolism; Pedigree; Phenotype; Trimethylamine N-oxide; Whole Genome Sequencing; Japan; Frameshift; FMO3; Trimethylamine N-oxide; Fish-like odor syndrome; Large database
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2019.06.001

Flavin-containing monooxygenase 3 (FMO3) is a polymorphic xenobiotic- and dietary compound-metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped 428 Japanese subjects using traditional urinary phenotyping assays and identified two subjects with <20% FMO3 metabolic capacity. Both subjects had novel frameshift mutations. Proband 1 harbored a novel CC deletion resulting in p.[(Pro153Gln fs; Phe166Ter)] FMO3, which was in trans configuration with p.(Cys197Ter). Proband 2 harbored a novel T deletion resulting in p.[(Met211Arg fs; Val220Ter)] FMO3, which was in trans configuration with p.[(Val257Met; Met260Val)]. We also analyzed a new large Japanese database for novel single nucleotide substitutions of FMO3 and identified the following variants with very low frequencies (<∼0.1%): p.(Lys56Glu), p.(Ser112Asn), p.(Asn164Lys), p.(Gly191Cys), p.(Ile199Ser), p.(Pro248Thr), p.(Pro248Leu), p.(Asp286Tyr), and p.(Ala311Pro). Recombinant FMO3 proteins of the above and unanalyzed variants underwent kinetic analysis of their trimethylamine/benzydamine N-oxygenation activities. Gly191Cys, Ile199Ser, Asp286Tyr, and Ala311Pro variant FMO3 proteins exhibited severely decreased activities (Vmax/Km <5% of wild-type). Although these new variants were rare alleles in Japanese self-reported trimethylaminuria sufferers and in the large genomic database, we found that most Japanese individuals compound heterozygous or homozygous for any of these missense FMO3 variants or known severe mutations [e.g., p.(Cys197Ter)] had impaired FMO3-dependent N-oxygenation of malodorous trimethylamine. [Display omitted]