Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome

@article{Dolphin1997MissenseMI,
  title={Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome},
  author={Colin T. Dolphin and Azara Janmohamed and Robert L. Smith and Elizabeth A. Shephard and lan R Phillips},
  journal={Nature Genetics},
  year={1997},
  volume={17},
  pages={491-494}
}
Individuals with primary trimethylaminuria exhibit a body odour reminiscent of rotting fish, due to excessive excretion of trimethylamine (TMA; refs 1–3). The disorder, colloquially known as fish-odour syndrome, is inherited recessively as a defect in hepatic N-oxidation of dietary-derived TMA4–6 and cannot be considered benign, as sufferers may display a variety of psychosocial reactions, ranging from social isolation to clinical depression and attempted suicide6. TMA oxidation is catalyzed by… 
Sequence variations in the flavin‐containing mono‐oxygenase 3 gene (FMO3) in fish odour syndrome
TLDR
The mutation Pro153→Leu153 appears to be a recurrent cause of this distressing metabolic disorder, and two further missense mutations were identified on the other FMO3 allele.
Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FM03) gene in patients with fish-odour syndrome.
TLDR
Functional characterization of the S61, 1434 and W492 variants, via baculovirus-mediated expression in insect cells, confirmed that all three mutations either abolished, or severely attenuated, the capacity of the enzyme to catalyse TMA N-oxidation.
Trimethylaminuria and a human FMO3 mutation database
TLDR
A human FMO3 mutation database was created using MuStar, a locus‐specific database system for maintaining data about allelic variants and distributing these via the World Wide Web, and is accessible on the World wide Web via the URL http://human‐fmo3.ucl.ac.uk/Human_FMO3.
Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication.
TLDR
It is shown that mutations in the human flavin-containing monooxygenase isoform 3 gene ( FMO3) impair N -oxygenation of xenobiotics and are responsible for the trimethylaminuria phenotype.
Deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene causing trimethylaminuria
TLDR
Both alleles of the FMO3 gene for individual 2 were affected by mutations abolishing the catalytic activity of the enzyme, explaining the severe TMAU condition.
A novel mutation in the flavin-containing monooxygenase 3 gene, FM03, that causes fish-odour syndrome: activity of the mutant enzyme assessed by proton NMR spectroscopy.
TLDR
A novel causative mutation for primary trimethylaminuria is reported, identified in a young girl diagnosed by proton nuclear magnetic resonance (NMR) spectroscopy of her urine, and represents the genetic basis of the disorder in this individual.
Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort.
TLDR
It is concluded that one common mutation and an increasing number of private mutations in individuals of different ethnic origins cause TMAuria in this cohort of individuals ascertained in North America, defined by a reduction of TMA oxidation below 50% of normal with genotype-phenotype correlations.
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References

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TLDR
The family data support the hypothesis that trimethylaminuria is an inborn error in the ability to N-oxidize TMA which is inherited as an autosomal recessive trait and experience with this family suggests that an oral challenge dose with 600 mg of TMA may be used to identify carriers of the condition.
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TLDR
It is proposed that the use of human metabolic variants allows both a qualitative and quantitative assessment of retroverted metabolism as occurs with TMAO, and the principle may usefully be applied in other situations.
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TLDR
The inability to obtain flavin-containing monooxygenase 4 (FMO4) in heterologous systems has hampered efforts to characterize this isoform of the FMO gene family, and the difference in expression levels between FMO4 and elongated FMO3 appears to be related to translation rather than transcription.
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TLDR
The fish odour syndrome can be inherited in an autosomal recessive fashion and should be considered as a possible causative factor in patients complaining of body malodour.
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TLDR
Analysis of human metaphase chromosomes by in situ hybridization confirmed the mapping of FMO1 and localized this gene more precisely to 1q23-q25 and proposed the designation FMO3 for this gene as it is the third FMO gene to be mapped.
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TLDR
The purpose of the proposed nomenclature is to provide for the unambiguous identification of orthologous forms of mammalian FMOs, regardless of the species or tissue in question.
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TLDR
The substrate regioselectivity studies suggest that adult human liver FMO form D possesses a distinct substrate specificity compared with form A FMO from animal hepatic sources.
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TLDR
An open reading frame from yeast coding for a homologue of flavin containing monooxygenase (FMO) has been cloned into several Escherichia coli expression vectors and activity may represent the initial role of the FMO family of enzymes, giving rise to the multigene family of drug metabolizing enzymes seen in modern mammals.
Characterization of flavin-containing monooxygenase 5 (FMO5) cloned from human and guinea pig: evidence that the unique catalytic properties of FMO5 are not confined to the rabbit ortholog.
TLDR
Results indicate that the unique properties of FMO5 from rabbit are species-independent and that this form of the flavin-containing monooxygenase is not readily classified as a drug-metabolizing enzyme.
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