Mild trimethylaminuria caused by common variants in FM03 gene

Zschocke, Johannes; Kohlmueller, Dirk; Quak, Elfriede; Meißner, Thomas; Hoffmann, G. F.; Mayatepek, Ertan

doi:10.1016/s0140-6736(99)80019-1

Cited by 53 publications

(23 citation statements)

References 4 publications

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“…Previous investigation of the effects of polymorphism upon FMO3 function, both in vivo and in vitro, have focused on only a few non-synonymous SNPs, and different substrates, i.e. trimethylamine [3], ranitidine [6], benzydamine, methyl p-tolyl sulfide, and sulindac sulfide [8]. These studies demonstrated substrate-specific effects, as well as a large share of variation in FMO3 activity still unaccounted for.…”

Section: Discussionmentioning

confidence: 99%

“…The targets of FMO3, the most prominently expressed member in adult liver [1, 2], include dietary-derived tertiary amines, commonly prescribed drugs, agrichemicals, and nicotine. Rare mutation in FMO3 is associated with trimethylaminuria, ‘fish odor syndrome’, and there is some evidence that common variation in the gene also reduces enzyme activity and contributes to mild or transient symptoms [3]. However, the locus is highly polymorphic with many common coding and non-coding variants having putative functional effects [4, 5], including non-synonymous variants that appear to interact in cis [6].…”

Section: Introductionmentioning

confidence: 99%

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Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

Bloom

Murphy

Martínez

et al. 2013

Pharmacogenetics and Genomics

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Background Flavin-containing monooxygenases (FMO) catalyze the metabolism of nucleophilic heteroatom containing drugs and xenobiotics including nicotine. Rare mutations in FMO3 are responsible for defective N-oxygenation of dietary trimethylamine leading to trimethylaminuria, and common genetic variation in FMO3 has been linked to interindividual variability in metabolic function that may be substrate specific. Methods A genetic model of CYP2A6 function is used as a covariate to reveal functional polymorphism in FMO3 that indirectly influences the ratio of deuterated nicotine metabolized to cotinine following oral administration. The association is tested between FMO3 haplotype and cigarette consumption in a set of nicotine dependent smokers. Results FMO3 haplotype, based on all common coding variants in Europeans, significantly predicts nicotine metabolism and accounts for approximately 2% of variance in the apparent percent of nicotine metabolized to cotinine. The metabolic ratio is not associated with FMO2 haplotype or an FMO1 expression quantitative trait locus (eQTL). Cross validation demonstrates calculated FMO3 haplotype parameters to be robust and significantly improve the predictive nicotine metabolism model over CYP2A6 genotype alone. Functional classes of FMO3 haplotypes, as determined by their influence on nicotine metabolism to cotinine, are also significantly associated with cigarettes per day (CPD) in nicotine dependent European Americans (n=1,025, p=0.04), and significantly interact (p=0.016) with CYP2A6 genotype to predict CPD. Conclusion These findings suggest that common polymorphisms in FMO3 influence nicotine clearance, and that these genetic variants in turn influence cigarette consumption.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

Bloom

Murphy

Martínez

et al. 2013

Pharmacogenetics and Genomics

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“…Individuals diagnosed with trimethylaminuria have a decrease in FMO3 enzyme activity [18,[115][116][117][118][119][120][121][122][123][124][125][126][127][128] and a database has been established to maintain information on human FMO3 variants [129]. Currently, twenty-four missense, three nonsense, and one gross deletion mutation have been reported in the database [129].…”

Section: Gene Responsible For Expression Of Fmo3 Enzymementioning

confidence: 99%

Trimethylamine: Metabolic, Pharmacokinetic and Safety Aspects

Bain¹,

Fornasini²,

Evans

2005

CDM

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Trimethylamine (TMA) is a volatile tertiary aliphatic amine that is derived from the diet either directly from the consumption of foods containing TMA, or by the intake of food containing precursors to TMA such as trimethylamine-N-oxide (TMNO), choline and L-carnitine. Following oral absorption in humans, TMA undergoes efficient N-oxidation to TMNO, a reaction catalyzed by the flavin-containing monooxygenase (FMO) isoform 3 enzyme. TMNO subsequently undergoes excretion in the urine, although, evidence also suggests that metabolic retro-reduction of TMNO can occur. Whilst the pharmacokinetics of TMA and TMNO has not been fully elucidated in humans, a number of studies provide information on the likely fate of dietary derived TMA. Trimethylaminuria is a condition that is characterized by a deficiency in FMO3 enzyme activity, resulting in the excretion of increased amounts of TMA in bodily fluids such as urine and sweat, and breath. A human FMO3 database has been established and currently twenty-eight variants of the FMO3 gene have been reported including twenty-four missense, three nonsense, and one gross deletion mutation. Whilst TMA and TMNO are generally regarded as non-toxic substances, they are of clinical interest because of their potential to form the carcinogen N-nitrosodimethylamine.

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“…This is due to a defect in the normal production of the enzyme FMO 3. [23] as a result of which, the body loses the ability to properly break down TMA from precursor compounds in food digestion into TMAO. TMA then builds up and is released in the person's sweat, urine and breath, giving off a strong fishy odor or strong body odor.…”

Section: Discussionmentioning

confidence: 99%

A rare case of fish odor syndrome presenting as depression

Khan¹,

Shagufta

2014

Indian J Psychiatry

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A young lady presents to the psychiatry out-patient department with depressive symptoms. Evaluation revealed long standing stressor in the form of a foul odor emanating from her body and over a period of time resulting in social withdrawal and depression with significant impairment of day-to-day functioning. A diagnosis of trimethylaminurea (fish odor syndrome) and adjustment disorder was arrived at. Careful empathetic handling with psychoeducation, behavioral and cognitive counseling and a short course of antidepressants helped her improve significantly with return to almost normal functioning.

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Mild trimethylaminuria caused by common variants in FM03 gene

Cited by 53 publications

References 4 publications

Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

Effects upon in-vivo nicotine metabolism reveal functional variation in FMO3 associated with cigarette consumption

Trimethylamine: Metabolic, Pharmacokinetic and Safety Aspects

A rare case of fish odor syndrome presenting as depression

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