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Rare but impaired flavin-containing monooxygenase 3 (FMO3) variants reported in a recently updated Japanese mega-databank of genome resources.
- Source :
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Drug metabolism and pharmacokinetics [Drug Metab Pharmacokinet] 2024 Apr; Vol. 55, pp. 100539. Date of Electronic Publication: 2023 Dec 22. - Publication Year :
- 2024
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Abstract
- Genetic variants of human flavin-containing monooxygenase 3 (FMO3) were investigated using an updated Japanese population panel containing 54,000 subjects (the previous panel contained 38,000 subjects). One stop codon mutation and six amino acid-substituted FMO3 variants were newly identified in the updated databank. Of these, two substituted variants (p.Thr329Ala and p.Arg492Trp) were previously identified in compound haplotypes with p.[(Glu158Lys; Glu308Gly)] and were associated with the metabolic disorder trimethylaminuria. Three recombinant FMO3 protein variants (p.Ser137Leu, p.Ala334Val, and p.Ile426Val) expressed in bacterial membranes had similar activities toward trimethylamine N-oxygenation (∼75-125 %) as wild-type FMO3 (117 min <superscript>-1</superscript> ); however, the recombinant novel FMO3 variant Phe313Ile showed moderately decreased FMO3 catalytic activity (∼20 % of wild-type). Because of the known deleterious effects of FMO3 C-terminal stop codons, the novel truncated FMO3 Gly184Ter variant was suspected to be inactive. To easily identify the four impaired FMO3 variants (one stop codon mutation and three amino-acid substitutions) in the clinical setting, simple confirmation methods for these FMO3 variants are proposed using polymerase chain reaction/restriction fragment length polymorphism or allele-specific PCR methods. The updated whole-genome sequence data and kinetic analyses revealed that four of the seven single-nucleotide nonsense or missense FMO3 variants had moderately or severely impaired activity toward trimethylamine N-oxygenation.<br />Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest.<br /> (© 2023 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.)
- Subjects :
- Humans
Codon, Terminator
Japan
Oxygenases genetics
Oxygenases metabolism
Methylamines
Subjects
Details
- Language :
- English
- ISSN :
- 1880-0920
- Volume :
- 55
- Database :
- MEDLINE
- Journal :
- Drug metabolism and pharmacokinetics
- Publication Type :
- Academic Journal
- Accession number :
- 38280279
- Full Text :
- https://doi.org/10.1016/j.dmpk.2023.100539