Genetic variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects identified by phenotyping for trimethylaminuria and found in a database of genome resources.
Drug Metab Pharmacokinet
; 38: 100387, 2021 Jun.
Article
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| MEDLINE
| ID: mdl-33831674
ABSTRACT
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.
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Base de datos:
MEDLINE
Asunto principal:
Oxigenasas
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Polimorfismo de Nucleótido Simple
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Pueblo Asiatico
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Errores Innatos del Metabolismo
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Metilaminas
Idioma:
En
Revista:
Drug Metab Pharmacokinet
Asunto de la revista:
FARMACOLOGIA
/
METABOLISMO
Año:
2021
Tipo del documento:
Article