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

Makiko Shimizu, Hiromi Yoda, Komei Nakakuki, Aoi Saso, Iria Saito, Eiji Hishinuma, Sakae Saito, Masahiro Hiratsuka, Hiroshi Yamazaki

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)334-339
Number of pages6
JournalDrug metabolism and pharmacokinetics
Volume34
Issue number5
DOIs
Publication statusPublished - 2019 Oct

Keywords

  • FMO3
  • Fish-like odor syndrome
  • Frameshift
  • Large database
  • Trimethylamine N-oxide

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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