New FMO3 paper : Norwegian family with novel FMO3 mutation

Another FMO3 paper was published on pubmed this week. This one involves Drs. Phillips and Shephard of London, who have a long history in FMO3/TMAU research. The paper is an observation of a Norwegian Family carrying an FMO3 mutant (a new one). Sadly this type of anecdotal paper makes up the bulk of FMO3/TMAU research. Especially recently; as opposed to big trials making breakthroughs.

The paper also shows the gap between researchers and sufferers, since the girl seems to have presented with a body odor problem, but since she doesn't fit the strict definition of TMAU by DNA (i.e. autosomal recessive) they are predicting her as a 'childhood' case. We will only be able to see if this is the case in 10 years or so.

She seems to have one copy of a 'new' severe mutation, which her mother also had a copy of. Her father seemed to have 2 other variant copies of FMO3, but she hadn't received either of them (?)

It again highlights the gray area of defining TMAU. At the moment researchers will try to shoehorn the definition into their own strict rules. Meanwhile the patient either has a transient smell problem or not. If they do have a smell problem, then the patient is the correct definition and the rules need changed (in this case we need to wait and see).

In the end, they at least found yet another 'novel' mutant to add to the list of mutants. How many more of these mutants will be found is unknown, but most of these anecdotal papers seem to be new mutants nowadays.

A novel mutation in the flavin-containing monooxygenase 3 gene (FMO3) of a Norwegian family causes trimethylaminuria


Allerston CK, Vetti HH, Houge G, Phillips IR, Shephard EA.

Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK.

Loss-of-function mutations in the flavin-containing monooxygenase 3 gene (FMO3) cause the inherited disorder trimethylaminuria (TMAuria), or fish-odour syndrome. Here we describe the identification in a family from northern Norway of a novel causative mutation of TMAuria. A female child within the family presented with a TMAuria-like phenotype. The child and her mother were found to be heterozygous for a novel mutation (R238Q) in exon 6 of FMO3. The child's father lacked this mutation, but was heterozygous for a double polymorphic variant, E158K/E308G, which was not present in the child. During a consultation with her doctor the mother mentioned an uncle whom she remembered as having a strong body odour. This discussion led to genetic counselling of the uncle and analysis of his DNA showed him to be homozygous for the R238Q mutation. Analysis of the mutant FMO3 expressed in bacteria revealed that the R238Q mutation abolished catalytic activity of the enzyme and is thus a causative mutation for TMAuria. The specificity constant (k(cat)/K(M)) of the K158/G308 variant was 43% of that of ancestral FMO3. Because the child is heterozygous for the R238Q mutation and no other mutation known to cause TMAuria was detected in her DNA she is predicted to suffer from transient childhood TMAuria, whereas her great-uncle has primary TMAuria.

http://www.ncbi.nlm.nih.gov/pubmed/19577495

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related links:
NIH GeneReviews page on trimethylaminuria
Pubmed search : Shephard EA
Professor EA Shephard UCL page
Pubmed search : Phillips IR

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