Rare but impaired flavin-containing monooxygenase 3 (FMO3) variants reported in a recently updated Japanese mega-databank of genome resources
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...
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| Published in | Drug metabolism and pharmacokinetics Vol. 55; p. 100539 |
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| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
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England
Elsevier Ltd
01.04.2024
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1347-4367 1880-0920 1880-0920 |
| DOI | 10.1016/j.dmpk.2023.100539 |
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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−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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| AbstractList | 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.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. 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 ); 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. 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. [Display omitted] |
| ArticleNumber | 100539 |
| Author | Hishinuma, Eiji Yamazaki, Hiroshi Hiratsuka, Masahiro Makiguchi, Miaki Saito, Sakae Shimizu, Makiko |
| Author_xml | – sequence: 1 givenname: Makiko orcidid: 0000-0002-2508-4031 surname: Shimizu fullname: Shimizu, Makiko organization: Showa Pharmaceutical University, Tokyo, Japan – sequence: 2 givenname: Miaki orcidid: 0009-0009-0736-8901 surname: Makiguchi fullname: Makiguchi, Miaki organization: Showa Pharmaceutical University, Tokyo, Japan – sequence: 3 givenname: Eiji orcidid: 0000-0001-8644-5120 surname: Hishinuma fullname: Hishinuma, Eiji organization: Advanced Research Center for Innovations in Next-Generation Medicine and Tohoku Medical Megabank Organization, Sendai, Japan – sequence: 4 givenname: Sakae surname: Saito fullname: Saito, Sakae organization: Advanced Research Center for Innovations in Next-Generation Medicine and Tohoku Medical Megabank Organization, Sendai, Japan – sequence: 5 givenname: Masahiro orcidid: 0000-0002-3767-7686 surname: Hiratsuka fullname: Hiratsuka, Masahiro organization: Advanced Research Center for Innovations in Next-Generation Medicine and Tohoku Medical Megabank Organization, Sendai, Japan – sequence: 6 givenname: Hiroshi orcidid: 0000-0002-1068-4261 surname: Yamazaki fullname: Yamazaki, Hiroshi email: hyamazak@ac.shoyaku.ac.jp organization: Showa Pharmaceutical University, Tokyo, Japan |
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| Cites_doi | 10.1038/ng1297-491 10.1080/00498254.2018.1539279 10.1016/j.dmpk.2021.100420 10.1016/j.ymgme.2012.06.014 10.1124/dmd.106.013094 10.1186/s12881-017-0369-8 10.1007/s00204-022-03304-3 10.1124/dmd.123.001310 10.1016/j.pharmthera.2005.01.001 10.1016/j.dmpk.2023.100490 10.1016/j.abb.2020.108663 10.1038/s41598-017-15224-9 10.1155/2019/2137629 10.1124/dmd.121.000742 10.1016/j.dmpk.2019.06.001 10.1124/dmd.121.000739 10.1016/S0021-9258(19)85592-8 10.1016/j.dmpk.2022.100465 10.1016/S0006-2952(98)00218-4 10.1007/s00228-020-03024-6 10.1016/j.dmpk.2021.100387 10.1093/hmg/7.5.839 10.2133/dmpk.21.245 10.1016/j.ymgme.2006.08.008 10.1016/S0021-9258(18)50388-4 10.1080/00498254.2019.1643515 10.1016/j.dmpk.2023.100528 |
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