Crowdfunded Monell TMAU paper published in Journal

Monell-based new TMAU paper published this week.
Conclusion : Enzymes other than FMO3 may be at fault for TMAU.
Based on exome testing 10 samples from their TMAU archive.
Study was funded by community crowdfund campaign ($33.5k ?).
Community donated to NORD TMAU Fund circa 2011.

Long-time readers may recall an energetic crowdfund-type campaign around 2009 to raise $25k for the NORD TMAU Fund. The aim was to fund a research study by Monell Chemical Senses Center, which has a long history of interest in  TMAU.

Paper published in Medical Journal
The research team kindly put the paper on an open source online site last fall to view, and now it's been published in an official Medical Journal (BMC Medical Genetics). This gives it more prestige and publicity (e.g. appearing on pubmed).

Genetic analysis of impaired trimethylamine metabolism using whole exome sequencing
(Full paper)

Purpose of the paper (first impression) :
With the limited funding, the aim seems to have been to re-look at 10 TMAU1 cases they had previously assessed that were +ve for the TMAU biochemical (urine) test but not the FMO3 DNA test. That is : TMAU1 for urine, but not the FMO3 DNA test.

Testing the genes (Exome testing)
It looks like they Exome tested the DNA to look for any other gene faults that may explain the +ve TMAU biochemical result. Exome testing means testing other protein DNA genes.

Conclusion 
They seem to conclude that faults at other genes may explain the +ve biochemical TMAU result. This would mean genetic TMAU may be caused by genes other than FMO3.

The above overview of the paper is very much a layperson first-impression overview.  
It will be interesting to read any reader views on the paper.

Links :

Science Daily : (Press release from Monell)

Abstract of the paper

Genetic analysis of impaired trimethylamine metabolism using whole exome sequencing

Full paper : link

Background

Trimethylaminuria (TMAU) is a genetic disorder whereby people cannot convert trimethylamine (TMA) to its oxidized form (TMAO), a process that requires the liver enzyme FMO3. Loss-of-function variants in the FMO3 gene are a known cause of TMAU. In addition to the inability to metabolize TMA precursors like choline, patients often emit a characteristic odor because while TMAO is odorless, TMA has a fishy smell. The Monell Chemical Senses Center is a research institute with a program to evaluate people with odor complaints for TMAU.

Methods

Here we evaluated ten subjects by (1) odor evaluation by a trained sensory panel, (2) analysis of their urine concentration of TMA relative to TMAO before and after choline ingestion, and (3) whole exome sequencing as well as subsequent variant analysis of all ten samples to investigate the genetics of TMAU.

Results

While all subjects reported they often emitted a fish-like odor, none had this malodor during sensory evaluation. However, all were impaired in their ability to produce >90% TMAO/TMA in their urine and thus met the criteria for TMAU. To probe for genetic causes, the exome of each subject was sequenced, and variants were filtered by genes with a known (FMO3) or expected effect on TMA metabolism function (other oxidoreductases). We filtered the remaining variants by allele frequency and predicated functional effects. We identified one subject that had a rare loss-of-function FMO3 variant and six with more common decreased-function variants. In other oxidoreductases genes, five subjects had four novel rare single-nucleotide polymorphisms as well as one rare insertion/deletion. Novel in this context means no investigators have previously linked these variants to TMAU although they are in dbSNP.

Conclusions

Thus, variants in genes other than FMO3 may cause TMAU and the genetic variants identified here serve as a starting point for future studies of impaired TMA metabolism.

https://www.sciencedaily.com/releases/2017/02/170215084717.htm  

get New Posts by EMAIL : Enter your email address :

---

A EURORDIS and NORD Member Organization