Twenty years ago Trimethylaminuria (TMAU), also known as fish odor syndrome, was linked to mutations in the gene coding an enzyme named flavin-containing monooxygenase 3 (FMO3). The flavin-containing monooxygenase (FMO) protein family specializes in the oxidation of xeno-substrates - chemicals foreign to the body. The chemicals processed by monooxygenases, particularly tertiary

acyclic and cyclic amines, are introduced into the body from the diet (e.g. from fish, eggs), medicines (such as mental health drugs imipramine, clozapine, and amphetamine, cancer drugs/hormones such as tamoxifen and NSAID Sulindac sulfide), stimulants (nicotine) and other environmental exposures. FMO enzymes convert these compounds to stable N-oxides,  facilitating the excretion from the body. The FMO3 enzyme, produced in the liver, is responsible for breaking down nitrogen-containing compounds mostly derived from the diet. In a healthy individual, 95% or more of fish-and-garbage-smelling by-product trimethylamine (TMA) is converted by this enzyme to non-odorous trimethylamine N-oxide (TMA N-oxide).

The recessive disorder trimethylaminuria (TMAU) was originally thought to be caused exclusively by defects in the FMO3 gene. 3 major faults were initially discovered in 1997, but the number grew to 40 in 2011. Genetic study published 3 years ago suggested there could be multiple impairments of genes and their protein products along the FMO3 metabolic pathway. Genes possibly implicated in TMAU included those with oxidoreductase function (such as PYROXD2, Pyridine Nucleotide-Disulphide Oxidoreductase) and a DMGDH (dimethylglycine dehydrogenase), see this 2001 case. Besides DMGDH, FMO3 may also interact with with hydroxy acid oxidase 2 (HAO2), NR1H4 (namely bile acid-associated nuclear receptor, FXR), CYP family (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP3A4, and CYP2D6), and 2,4-dienoyl-CoA reductase, ther members of the FMO family, additionalk members of the CYP family (CYP4F11, CYP2E1, and CYP7A1), diacylglycerol kinase-epsilon (DGKE), keratin 4 (KRT4), casein alpha S1 (CSN1S1), mannose binding lectin (MBL2), alcohol dehydrogenase 1C (ADH1C), ATPase, Cu2+ transporting β polypeptide (ATP7B), solute carrier organic anion transporter family, member 1B3 (SLCO1B3), DNA meiotic recombinase 1 (DMC1), guanylate cyclase soluble subunit α-3 (GUCY1A3), GC-box (GC), C6 alkyl side chains (C6), and proteoglycan 4 (PRG4).

A pilot study published this month identified two new genes - heat shock proteins and chaperones. As the authors say "Although, to date, there is little evidence of interaction between HSPA8 and FMO3, two possible mechanisms for further investigation can be considered. The first regards the role of HSPA8 in FMO3 folding, assembly, and stabilization. The second one is related to HSPA8 as mediator of FMO3 degradation."

This long list makes it hard to avoid ending this post with a cliché "more research is needed".

REFERENCES

  1.    Humbert, J. R., Hammond, K. B., Hathaway, W. E., Marcoux, J., O'Brien, D. Trimethylaminuria: the fish-odour syndrome. (Letter) Lancet 296: 770-771, 1970.

2.    Akerman, B. R., Chow, L., Forrest, S., Youil, R., Cashman, J., Treacy, E. P. Mutations in the flavin-containing monoxygenase (sic) form 3 (FMO3) gene cause trimethylaminuria, fish odour syndrome. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A53 only, 1997.

3.    Dolphin, C. T., Janmohamed, A., Smith, R. L., Shephard, E. A., Phillips, I. R. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nature Genet. 17: 491-494, 1997. 

4.    Phillips IR, Shephard EA. Flavin-containing monooxygenases: mutations, disease and drug response. Trends in pharmacological sciences. 2008 Jun 1;29(6):294-301.

5.    Hernandez, D., Addou, S., Lee, D., Orengo, C., Shephard, E. A., Phillips, I. R. Trimethylaminuria and a human FMO3 mutation database. Hum. Mutat. 22: 209-213, 2003.

6.    Guo Y, Hwang LD, Li J, Eades J, Yu CW, Mansfield C, Burdick-Will A, Chang X, Chen Y, Duke FF, Zhang J. Genetic analysis of impaired trimethylamine metabolism using whole exome sequencing. BMC medical genetics. 2017 Dec 1;18(1):11.

7.    Scimone C, Alibrandi S, Donato L, Esposito T, Sidoti A, D’Angelo R. Variants of the molecular chaperone hspa8 and hspa1a genes in trimethylaminuria: a pilot study. Euromediterranean biomedical journal 2020,15 (38) 157–160 (formerly: capsula eburnea)