Abstract
Polymorphic human flavin-containing monooxygenase 3 (FMO3) is associated with the inherited disorder trimethylaminuria. Several FMO3 variants have been observed in a variety of ethnic groups, including a Japanese cohort suffering from trimethylaminuria. The aim of this study was to screen another self-reported Japanese trimethylaminuria cohort for novel FMO3 variants and to investigate these new variants. Subjects with low FMO3 metabolic capacities were identified by measuring the urinary trimethylamine and trimethylamine N-oxide concentrationsin171 Japanese volunteers. The FMO3 genes from these subjects and their family members were then sequenced. Heterozygotes or homozygotes for novel single-nucleotide polymorphisms c.20 T>C p.(Ile7Thr), c.122 G>A p.(Trp41Ter), c.127T>A p.(Phe43Ile), c.488 T>C p.(Leu163Pro), and c.1127G>A p.(Gly376Glu) and a heterozygote for the novel duplication c.850_860dupTTTAACGATGA p.(Glu287AspfsTer17) were identified. In addition, the known (but as yet uncharacterized) single-nucleotide polymorphism c.929 C>T p.(Ser310Leu) was found. Pedigree analysis revealed the p.(Ser310Leu) FMO3 allele in cis configuration with c.929 C>T p.(Glu158Lys). These variant FMO3 proteins recombinantly expressed in Escherichia coli membranes exhibited decreased N-oxygenation activities toward trimethylamine and benzydamine. Although the allele frequencies of these seven variants were low, the present results suggest that individuals homozygous or heterozygous for any of these novel missense or duplicationFMO3 variants or known nonsense mutations such as p.(Cys197Ter) may possess abnormal activities toward trimethylamine N-oxygenation.
Highlights
Polymorphic human flavin-containing monooxygenase 3 (FMO3, EC 1.14.13.8) is associated with the inherited disorder trimethylaminuria [1,2] — the inability to metabolize odorous dietary-derived trimethylamine to its non-odorous N-oxide [3,4]
FMO3 metabolic capacity (% of total trimethylamine excreted as trimethylamine N-oxide) was determined in volunteers with selfreported trimethylaminuria
Six novel FMO3 variants with impaired trimethylamine and benzydamine N-oxygenation capacity were discovered in a Japanese population with self-reported trimethylaminuria; these variants are likely causative of trimethylaminuria (Fig. 1)
Summary
Polymorphic human flavin-containing monooxygenase 3 (FMO3, EC 1.14.13.8) is associated with the inherited disorder trimethylaminuria [1,2] — the inability to metabolize odorous dietary-derived trimethylamine to its non-odorous N-oxide [3,4]. Rare loss-of-function mutations [1] that cause the disorder have been reported. Decreased or abolished functional activities with respect to trimethylamine Noxygenation, resulting in trimethylaminuria, are caused mainly by single nucleotide polymorphisms of the FMO3 gene. Such FMO3 polymorphisms have been reported in the literature [5,6,7,8,9]. FMO3 mutations resulting in the amino acid substitutions p.(Glu158Lys), p.(Val257Met), and p.(Glu308Gly) have been reported as common FMO3 gene variants in the International HapMap project (http://www.hapmap.org) in multiple ethnic populations. Differences in terms of frequency of occurrence of the FMO3 variants have been recognized in Caucasian and Asian populations [10]
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