FMO3 Genetics class : part 1

It is hoped readers may be interested in a series of posts about the technical side of Trimethylaminuria (TMAU), especially genetic TMAU. Genetic TMAU is deemed to be caused by a deficiency (of some degree) of the flavin mono-oxygenase Isoform 3 enzyme (FMO3). It seems the deficiency can be generally constant or can be only at certain times, such as menstruation, depending on the variant causing it.

A simplistic way to think of the genetic building of FMO3 is to think of the FMO3 protein being made up from a series of 532 amino acids in a particular sequence. An analogy to use would be a ladder with 532 rungs. If at any rung (codon) there is a fault (variant), it can cause problems depending on the expected severity of the variant. Also, a nonsense mutation is where the building of the rungs is stopped completely at a certain rung, leaving an unfinished 'ladder' to be turned into the FMO3 protein.

At each rung in the ladder, the person can potentially have a variant on one side (heterozygous) or both sides (homozygous), or be completely normal.

A common 'variant' in humans is known as E158K. It is estimated that perhaps 50% of the population are at least heterozygous for this variant. It means at rung (codon) 158, the amino acid should be glutamic acid (E), but instead is lysine (K). On it's own, this is such a small error that no negative effect on FMO3 function is expected even if the person has variant E158K on both sides (homozygous) of rung 158.

Another common variant is E308G. Using the ladder analogy again, this is a common variant at 'rung' 308. It is meant to be lysine (E), but instead is glycine (G). Again, whether the person has one copy (heterozygous) or 2 (homozygous), it is such a minor fault that normal function is predicted.

However, it now seems expected that if someone is at least heterozygous for both the above variants on the same side, i.e., on the same chromosome, from the same parent, there is predicted to be a loss of function to some degree, e.g., 80% TMA to TMAO conversion, rather than over 95%. Possibly this combination may make up most cases of genetic TMAU - they would likely be 'mild' genetic TMAU cases.

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The table of symbols for amino acids
Table of human FMO3 allelic variants (to be updated soon)

E158K estimates (at least one copy) in USA population :
Caucasian 40%
African-American 40%
Hispanic 33%
Asian 14%

E308G estimates (at least one copy) in USA population :
Caucasian 19%
African American 5%
Hispanic 9%
Asian 16%

2.5% of Caucasians are estimated to have one copy of both E158K and E308G (known as a haplotype), but as long as they are not on the same chromosome then no loss of function is currently predicted.