A family study of compound variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects found by urinary phenotyping for trimethylaminuria

• Published in: Drug metabolism and pharmacokinetics Vol. 50; p. 100490
• Main Authors: Shimizu, Makiko, Yamamoto, Akane, Makiguchi, Miaki, Shimamura, Erika, Yokota, Yuka, Harano, Mizuki, Yamazaki, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2023
• Subjects: Child; East Asian People - genetics; Familial study; Female; FMO3; Humans; Infant; Metabolism, Inborn Errors - genetics; Oxygenases - genetics; Oxygenases - metabolism; Polymerase chain reaction; Restriction fragment length polymorphism; Polymerase chain reaction; Familial study; Restriction fragment length polymorphism; FMO3
• ISSN: 1347-4367; 1880-0920; 1880-0920
• DOI: 10.1016/j.dmpk.2023.100490

Phenotype–gene analyses and the increasing availability of mega-databases have revealed the impaired human flavin-containing monooxygenase 3 (FMO3) variants associated with the metabolic disorder trimethylaminuria. In this study, a novel compound variant of FMO3, p.[(Val58Ile; Tyr229His)], was identified in a 1-year-old Japanese girl who had impaired FMO3 metabolic capacity (70%) in terms of urinary trimethylamine N-oxide excretion levels divided by total levels of trimethylamine and its N-oxide. One cousin in the family had the same p.[(Val58Ile); (Tyr229His)]; [(Glu158Lys; Glu308Gly)] FMO3 haplotype and had a similar FMO3 metabolic capacity (69%). In a family study, the novel p.[(Val58Ile); (Tyr229His)] compound FMO3 variant was also detected in the proband 1's mother and aunt. Another novel compound FMO3 variant p.[(Glu158Lys; Met260Lys; Glu308Gly; Ile426Thr)] was identified in a 7-year-old girl, proband 2. This novel compound FMO3 variant was inherited from her mother. Recombinant FMO3 Val58Ile; Tyr229His variant and Glu158Lys; Met260Lys; Glu308Gly; Ile426Thr variant showed moderately decreased capacities for trimethylamine N-oxygenation compared to wild-type FMO3. Analysis of trimethylaminuria phenotypes in family studies has revealed compound missense FMO3 variants that impair FMO3-mediated N-oxygenation in Japanese subjects; moreover, these variants could result in modified drug clearances. [Display omitted]