FMO3 coding sequence for 'wild type'

This page contains the amino acid sequence to make up an FMO3 protein. The coding sequence for FMO3 is 532 amino acids long (and a stop codon), and to read them here you group the letters into blocks of 3 (eg GGA). The sequence shown is the 'wild type' sequence, which presumably would be the sequence for a 'normal' FMO3 protein (until proven otherwise by new research). This sequence would be repeated in the other parent, giving the person 2 strands of 'normal' wild-type protein. Most people probably have little changes from this sequence which probably do not make enough difference to affect the person in practice. It's when the changes can affect the building of proper FMO3 protein that people can have problems. Sometimes this can be what are known as single nucleotide polymorphisms (SNP) where the wrong amino acid is built in a codon. If someone is a carrier of this wrong amino acid, sometimes if they have another SNP in their FMO3 code they can both affect the function of the FMO3 protein. This is known as being a 'compound heterozygote'. An example would be common SNPs at codons 158 and 308 which when on the same strand (from the same parent) are known to likely decrease FMO3 function. SNPs are common little errors (missense mutations). There are other errors which can have an even more profound affect, such as nonsense mutations or deletions.

FMO3 coding sequence

so on one allelle, the coding for the first 2 codons would be :
1. ATG (methionine)
2. GGG (glycine)

On both allelles (one from each parent) it would look like :

AA
TT
GG

GG
GG
GG

FMO3 DNA has 9 exons. The coding sequence for FMO3 is on 8 of the 9 exons (the first exon does not seem to play a role)

The genetic structure can be thought of as exons, coding exons, introns and any other parts :
the coding exons (with the information needed to make the protein. The important bit !)
Any other exons (not coding)
Introns (which seem to be 'junk DNA')
Any other parts that play a role in making the DNA function, such as the promoter region

Unfortunately, although introns seem to be 'junk DNA', it seems that if there are mutants in the introns they could stop the proper building of an FMO3 protein. This may be why some people seem to have sub-normal TMAU urine results but this is not confirmed by the DNA test, because the DNA test only looks at coding exons.

Dr Richard Kirk kindly gave us this quote in an earlier post :

A :Thank you for your email.
Our FMO3 DNA test is done by sequencing all the parts of the FMO3 gene that code for the FMO3 protein/enzyme ('exons' in genetics terms). This means that we do pick up neutral polymorphisms and variants, as well as pathogenic mutations. In particular, we can and do detect the p.[Glu138Lys;Glu308Gly] variant haplotype that is mentioned in the 2007 paper, and others. If we find this variant haplotype on one or both copies of the gene, we include it in our reports.
There are certainly individuals that appear to have primary TMAU on the urine test, but nothing on our DNA test.
Although our test will pick up all the mutations that have been described in this gene, we cannot exclude rare mutation mechanisms such as mutations deep within introns (the non-coding DNA between the exons) or mutations affecting the controlling mechanisms for the gene. There is also a theoretical possibility that other related proteins/enzymes could be affected. Unfortunately, investigating these possibilities would be research, and beyond the current scope of a diagnostic service like ours.
I hope this information is of help.

...The one addition I would make is that we also cannot exclude a non-genetic cause for a 'primary' result on the urine test. Further biochemical and microbiological follow-up can sometimes help to give a full picture. Unfortunately in some of these cases our current laboratory testing cannot come up with a final answer.

Richard Kirk MSc FRCPath
Lead Clinical Scientist - Inborn Errors of Metabolism Section
Sheffield Diagnostic Genetics Service

Sheffield Children's NHS Foundation Trust
Western Bank
SHEFFIELD S10 2TH
UK

FMO3 question in blog

MEBO Research plans to put more in-depth information on how to read FMO3 DNA on our website. For now, we have an example of how one 'wild-type' allelle for building an FMO3 protein would look like.

FMO3 532 coding sequence on MEBO Research website