Rare but impaired flavin-containing monooxygenase 3 (FMO3) variants reported in a recently updated Japanese mega-databank of genome resources

被引:1
作者
Shimizu, Makiko [1 ]
Makiguchi, Miaki [1 ]
Hishinuma, Eiji [2 ,3 ]
Saito, Sakae [2 ,3 ]
Hiratsuka, Masahiro [2 ,3 ,4 ,5 ]
Yamazaki, Hiroshi [1 ,6 ]
机构
[1] Showa Pharmaceut Univ, Tokyo, Japan
[2] Adv Res Ctr Innovat Next Generat Med, Sendai, Japan
[3] Tohoku Med Megabank Org, Sendai, Japan
[4] Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Japan
[5] Tohoku Univ Hosp, Dept Pharmaceut Sci, Sendai, Japan
[6] Showa Pharmaceut Univ, Lab Drug Metab & Pharmacokinet, 3-3165 Higashi Tamagawa Gakuen, Machida, Tokyo 1948543, Japan
基金
日本学术振兴会;
关键词
FMO; Trimethylamine; Tohoku medical mega bank; GENETIC-VARIANTS; N-OXYGENATION; TRIMETHYLAMINURIA; POLYMORPHISMS; SPECIFICITY; MUTATIONS;
D O I
10.1016/j.dmpk.2023.100539
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 -1); 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.
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页数:4
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