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.

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. Drug Metab Pharmacokinet. 2019 Jun 27;: Authors: Shimizu M, Yoda H, Nakakuki K, Saso A, Saito I, Hishinuma E, Saito S, Hiratsuka M, Yamazaki H 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 activ...
Source: Drug Metabolism and Pharmacokinetics - Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research