Messina lab paper on FMO3 'haplotypes'

TMAU is taught as : person is normal or severe.

Severe is 2 very rare mutations as  a couple ... homozygous.

The Dr/patient approach to TMAU is ... do urine test. If negative, take no further action. 

If positive, do FMO3 gene test.

Re urine test :   

positive ... then test FMO3 gene. 'severe and rare' will show, but also many FMO3 results will not match concept of homozygous/coupled rare mutations. Most will be a patchwork of common variants taught as harmless etc. Dr not too bothered. 

negative ... and so do not test FMO3 gene (so all the 'FMO3 patchwork' cases in this group aren't spotted.)

a clinical lab in Messina Italy seems to be doing very relevant clinical TMAU/FMO3 that may help sufferers, especially those who are negative in the urine test (probably 95% cases).

They seem to be looking in to the theory that most cases of TMAU are not 'rare severe homozygous' cases as is taught, but rather combinations of mild common (or common taught as harmless) variants (heterozygous), which are known as Haplotypes. Or Compound Heterozygotes.

The blog opinion is that this theory is correct and will make up 95%+ of the cases, most of which will currently pass the urine test.

An analogy would be can someone walk or not.

Currently TMAU diagnosis and teaching is : 1 or other.

But we know many can't walk well or very far etc. Crutches, sprained ankles, whatever.

This gray-area is probably where most TMAU cases lie. Transient.

So for a clinical lab to put this theory forward in a paper would be very beneficial to the TMAU community in the sense it may change the attitude of the clinical health professionals for a diagnosis.

Probably they are still being conservative, in that they are likely trying to match positive urine cases to FMO3 results that don't fit the 'rare severe variant' teaching. This is already obvious, but nice for a lab to make a paper of it. 

Full Paper (link  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618768/  )

Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes

Simona Alibrandi, Fabiana Nicita, Luigi Donato, Concetta Scimone, Carmela Rinaldi, Rosalia D'Angelo, Antonina Sidoti

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy.

Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene FMO3, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The FMO3 screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of FMO3, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of FMO3 variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis.

Quotes:

"To date, 91 FMO3 variants were identified, and more than half of them are responsible for the TMAU phenotype (http://www.hgmd.cf.ac.uk/ac/index.php, accessed on 19 October 2021). Among the remaining variants, some are of uncertain clinical significance, while others are classified as “benign” and, therefore, should not affect the FMO3 enzyme activity

However, as such variants have a high frequency in TMAU patients, frequently without the contemporary presence of causative mutations, we hypothesized that their haplotypes could play a significant role in FMO3 activity reduction or alteration. To confirm this hypothesis, we performed a proteomic in silico analysis, using different platforms and software, with the final aim of revealing how these variant combinations could influence the enzyme folding, also simulating its dynamic behaviour with the TMA substrate."

Messina TMAU lab ask for DNA results !!!

In a previous post we mentioned Messina TMAU lab are always looking for FMO3 results from people who identify with TMAU. Although a small lab, it looks like their TMAU/FMO3 clinical research will continue. They are possibly 1 of only 2 labs (both small) who do direct TMAU/FMO3 research. The other lab in Argentina was only recently noticed, and will be a new post.   

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