Clinical utility gene card for: Trimethylaminuria

Shephard, Elizabeth A.; Treacy, Eileen P.; Phillips, Ian

doi:10.1038/ejhg.2011.214

Cited by 15 publications

(10 citation statements)

References 35 publications

(33 reference statements)

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“…One hundred and two Japanese individuals self‐reporting with symptoms of TMAuria were analyzed for the metabolic capacity of FMO3, as measured by the percentage of total TMA, i.e., TMA plus TMA N ‐oxide, excreted in the urine as the N ‐oxide (Figure ). Of the 102 individuals, 78 (76%) displayed symptoms of TMAuria, as judged by urinary excretion of <90% of total TMA as TMA N ‐oxide, with the remaining 24 (24%) being unaffected, with a urinary excretion of >90% of total TMA as the N ‐oxide . TMAuria has been classified as severe or mild, based, respectively, on excretion of <60% or 60–90% of total TMA as TMA N ‐oxide .…”

Section: Resultsmentioning

confidence: 99%

“…Of the 102 individuals, 78 (76%) displayed symptoms of TMAuria, as judged by urinary excretion of <90% of total TMA as TMA N ‐oxide, with the remaining 24 (24%) being unaffected, with a urinary excretion of >90% of total TMA as the N ‐oxide . TMAuria has been classified as severe or mild, based, respectively, on excretion of <60% or 60–90% of total TMA as TMA N ‐oxide . However, this classification is based on studies of small numbers of individuals and has been refined, as outlined below, to reflect gaps in the spectrum of urinary excretion of total TMA as TMA N ‐oxide in the large cohort of individuals in the present study (see also Table , below).…”

Section: Resultsmentioning

confidence: 99%

“…FMO3 (MIM 136132), present in the liver, catalyzes the N‐ oxygenation of TMA to produce non‐odorous TMA N ‐oxide . Individuals with defective FMO3 suffer from the disorder trimethylaminuria [TMAuria (MIM 60279)] and excrete excessive amounts of TMA in bodily secretions, including sweat, urine and reproductive fluids . Consequently, they exhibit an unpleasant body and breath odour and suffer the social and psychological problems associated with body malodours .…”

Section: Introductionmentioning

confidence: 99%

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Relationships between flavin‐containing mono‐oxygenase 3 (FMO3) genotype and trimethylaminuria phenotype in a Japanese population

Shimizu

Allerston

Shephard

et al. 2014

Brit J Clinical Pharma

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AIMThe aim of this study was to investigate relationships between flavin-containing mono-oxygenase 3 (FMO3) genotype and phenotype (conversion of odorous trimethylamine into non-odorous trimethylamine N-oxide) in a large Japanese cohort suffering from trimethylaminuria. METHODSUrinary excretion of trimethylamine and trimethylamine N-oxide was determined for 102 volunteers with self-reporting symptoms of trimethylaminuria. For each we determined the sequence of the entire coding region, plus 1.3 kb of flanking intronic and 2.5 kb of the upstream region of the FMO3 gene. The affect of upstream variants on transcription was determined with a reporter gene assay. RESULTSSeventy-eight subjects were diagnosed as suffering from trimethylaminuria, based on urinary excretion of <90% of total TMA as TMA N-oxide. Of these, 13 were classified as severe, 56 as moderate and nine as mild cases, excreting <43%, 48-70% and 73-83% of trimethylamine as trimethylamine N-oxide, respectively. Twenty-seven mutations were identified in FMO3, 15 in the coding region, of which eight abolish or severely impair FMO3 activity (Pro70Leu, Cys197fsX, Thr201Lys, Arg205Cys, Met260Val, Trp388Ter, Gln470Ter and Arg500Ter), and 12 in the upstream region. The mutations segregate into 19 haplotypes, including four different combinations of upstream mutations, each of which reduces transcriptional activity in comparison with the ancestral upstream sequence of FMO3. CONCLUSIONSComparisons of genotype and phenotype reveal that severe trimethylaminuria is caused by loss of function mutations in FMO3. For moderate and mild cases the situation is more complex, with most resulting from factors other than FMO3 genotype. Our results have implications for the diagnosis and management of the disorder. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Trimethylaminuria results from reduced capacity to convert trimethylamine to trimethylamine N-oxide, a reaction catalyzed by FMO3. • Mutations of FMO3 are known to cause trimethylaminuria, but an understanding of the phenotypic consequences of different FMO3 genotypes (haplotypes) is lacking. WHAT THIS STUDY ADDS• Severe trimethylaminuria is caused by mutations that severely impair FMO3 activity.• Most affected individuals present with moderate or mild forms of the disorder, due to factors other than FMO3 genotype.• Although for the majority of sufferers sequencing of FMO3 would not be informative, reduction of trimethylamine burden should prove beneficial.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Relationships between flavin‐containing mono‐oxygenase 3 (FMO3) genotype and trimethylaminuria phenotype in a Japanese population

Shimizu

Allerston

Shephard

et al. 2014

Brit J Clinical Pharma

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“…This fish-odour syndrome (the other name for TMAU) is caused by a deficiency in functional FMO3. This is mainly a genetic disorder (autosomal recessive) corresponding to a rare inborn disease, with about 0.5-1.0% of the UK population being heterozygous carriers in the white UK population [43][44][45]. Therefore, it Figure 2.…”

Section: The Peculiar Case Of Trimethylaminuriamentioning

confidence: 99%

Archaebiotics: Archaea as Pharmabiotics for Treating Chronic Disease in Humans?

Hania¹,

Ballet²,

Vandeckerkove³

et al. 2017

Archaea - New Biocatalysts, Novel Pharmaceuticals and Various Biotechnological Applications

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Recent findings highlight the role of the human gut microbiota in various disorders. For example, atherosclerosis frequently seems to be the consequence of gut microbiotaderived metabolism of some dietary components. Pharmabiotics (i.e., live/dead microbes and microbe-derived substances) and probiotics (live microorganisms with a health benefit when administered in adequate amounts) are a means to counteract these deleterious effects. Among the latter, microbes now being used or, being currently developed, are bacteria and eukaryotes (yeasts), so omitting the third domain of life-the archaea, despite their unique properties that could be of great interest to human health. Here, we promote the idea that some specific archaea are potential next-generation probiotics. This is based on an innovative example of the bioremediation of a gut microbial metabolite. Indeed, besides the fact that they are archaea (i.e. originating from a domain of life from which no pathogens of humans/animals/plants are currently known), they are rationally selected based on (i) being naturally human-hosted, (ii) having a unique metabolism not performed by other human gut microbes, (iii) depleting a deleterious atherogenic compound generated by the human gut microbiota and (iv) generating a health inert gas.

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“…Individuals suffering from trimethylaminuria have FMO3 with a decreased capacity to oxygenate free malodorous trimethylamine to non-odorous trimethylamine N-oxide [9]. This is the case for individuals with causative FMO3 gene mutations found in North American and European populations [10].…”

Section: Introductionmentioning

confidence: 98%