TY - JOUR
T1 - Genetic variants of flavin-containing monooxygenase 3 (FMO3) derived from Japanese subjects with the trimethylaminuria phenotype and whole-genome sequence data from a large Japanese database
AU - Shimizu, Makiko
AU - Yoda, Hiromi
AU - Nakakuki, Komei
AU - Saso, Aoi
AU - Saito, Iria
AU - Hishinuma, Eiji
AU - Saito, Sakae
AU - Hiratsuka, Masahiro
AU - Yamazaki, Hiroshi
N1 - Funding Information:
We thank all the volunteers for their participation in the follow-up study. We are grateful to Drs. Norie Murayama, and Yusuke Kamiya for their assistance, and we thank David Smallbones for copyediting a draft of this article. This work was supported partly by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research 16K08380 .
Publisher Copyright:
© 2019 The Japanese Society for the Study of Xenobiotics
PY - 2019/10
Y1 - 2019/10
N2 - Flavin-containing monooxygenase 3 (FMO3) is a polymorphic xenobiotic- and dietary compound-metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped 428 Japanese subjects using traditional urinary phenotyping assays and identified two subjects with <20% FMO3 metabolic capacity. Both subjects had novel frameshift mutations. Proband 1 harbored a novel CC deletion resulting in p.[(Pro153Gln fs; Phe166Ter)] FMO3, which was in trans configuration with p.(Cys197Ter). Proband 2 harbored a novel T deletion resulting in p.[(Met211Arg fs; Val220Ter)] FMO3, which was in trans configuration with p.[(Val257Met; Met260Val)]. We also analyzed a new large Japanese database for novel single nucleotide substitutions of FMO3 and identified the following variants with very low frequencies (<∼0.1%): p.(Lys56Glu), p.(Ser112Asn), p.(Asn164Lys), p.(Gly191Cys), p.(Ile199Ser), p.(Pro248Thr), p.(Pro248Leu), p.(Asp286Tyr), and p.(Ala311Pro). Recombinant FMO3 proteins of the above and unanalyzed variants underwent kinetic analysis of their trimethylamine/benzydamine N-oxygenation activities. Gly191Cys, Ile199Ser, Asp286Tyr, and Ala311Pro variant FMO3 proteins exhibited severely decreased activities (Vmax/Km <5% of wild-type). Although these new variants were rare alleles in Japanese self-reported trimethylaminuria sufferers and in the large genomic database, we found that most Japanese individuals compound heterozygous or homozygous for any of these missense FMO3 variants or known severe mutations [e.g., p.(Cys197Ter)] had impaired FMO3-dependent N-oxygenation of malodorous trimethylamine.
AB - Flavin-containing monooxygenase 3 (FMO3) is a polymorphic xenobiotic- and dietary compound-metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped 428 Japanese subjects using traditional urinary phenotyping assays and identified two subjects with <20% FMO3 metabolic capacity. Both subjects had novel frameshift mutations. Proband 1 harbored a novel CC deletion resulting in p.[(Pro153Gln fs; Phe166Ter)] FMO3, which was in trans configuration with p.(Cys197Ter). Proband 2 harbored a novel T deletion resulting in p.[(Met211Arg fs; Val220Ter)] FMO3, which was in trans configuration with p.[(Val257Met; Met260Val)]. We also analyzed a new large Japanese database for novel single nucleotide substitutions of FMO3 and identified the following variants with very low frequencies (<∼0.1%): p.(Lys56Glu), p.(Ser112Asn), p.(Asn164Lys), p.(Gly191Cys), p.(Ile199Ser), p.(Pro248Thr), p.(Pro248Leu), p.(Asp286Tyr), and p.(Ala311Pro). Recombinant FMO3 proteins of the above and unanalyzed variants underwent kinetic analysis of their trimethylamine/benzydamine N-oxygenation activities. Gly191Cys, Ile199Ser, Asp286Tyr, and Ala311Pro variant FMO3 proteins exhibited severely decreased activities (Vmax/Km <5% of wild-type). Although these new variants were rare alleles in Japanese self-reported trimethylaminuria sufferers and in the large genomic database, we found that most Japanese individuals compound heterozygous or homozygous for any of these missense FMO3 variants or known severe mutations [e.g., p.(Cys197Ter)] had impaired FMO3-dependent N-oxygenation of malodorous trimethylamine.
KW - FMO3
KW - Fish-like odor syndrome
KW - Frameshift
KW - Large database
KW - Trimethylamine N-oxide
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U2 - 10.1016/j.dmpk.2019.06.001
DO - 10.1016/j.dmpk.2019.06.001
M3 - Article
C2 - 31401033
AN - SCOPUS:85073085348
VL - 34
SP - 334
EP - 339
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
SN - 1347-4367
IS - 5
ER -