1. 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.
- Author
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Shimizu M, Yoda H, Nakakuki K, Saso A, Saito I, Hishinuma E, Saito S, Hiratsuka M, and Yamazaki H
- Subjects
- Child, Preschool, Female, Genetic Variation genetics, Humans, Japan, Male, Metabolism, Inborn Errors metabolism, Methylamines metabolism, Middle Aged, Oxygenases metabolism, Pedigree, Phenotype, Databases, Genetic, Metabolism, Inborn Errors genetics, Methylamines urine, Oxygenases genetics, Whole Genome Sequencing
- Abstract
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 (V
max /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., (Copyright © 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)- Published
- 2019
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