new Japanese FMO3/TMAU paper : Discovering some new variants ?

abstract to the paper

Variants in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population.

Shimizu M, Kobayashi Y, Hayashi S, Aoki Y, Yamazaki H

Loss-of-function mutations of flavin-containing monooxygenase 3 (FMO3), the enzyme responsible for trimethylamine N-oxygenation, cause the inherited disorder trimethylaminuria, or fish odor syndrome. The aim of this study was to further investigate the inter-individual variations of FMO3 activity in a Japanese cohort that we had studied previously. The subjects were 640 Japanese volunteers with self-reported trimethylaminuria; genomic DNA was sequenced in those that had 10-70% FMO3 metabolic capacity in urine tests...

Abstract : Variants in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population

This is a new FMO3/TMAU research paper by a group of Japanese researchers who have a long history in interest about FMO3 enzyme and trimethylaminuria. The information from the abstract seems quite limited, but it seems they DNA tested a large group of people they had previously urine tested for TMAU who had been positive for the urine test (Picking the results from those who had FMO3 capacity in their urine test between 10%-70%). It seems they may have found a few new variants that can affect FMO3 function. Also of interest is that is seems to say that being a 'carrier' of some of these new variants may be enough to make the person a sufferer.

We were kindly given a quote by Professor Ronald Hines who has a long history of interest in TMAU and FMO3. In particular it was put to Dr Hines if this meant some 'carriers' may be at risk of TMAU.

This is not autosomal dominance. Other than null variants (i.e., ones that result in a completely inactive enzyme), the impact of missense mutations (i.e., ones that result in a change in the amino acid at a given position) will vary from one variant to another. One also can observe variable impact depending on the compound being metabolized. Thus, one missense variant may reduce FMO3’s ability to oxidize TMA by 80% while another will only impact the enzyme’s ability to oxidize TMA by 20%. If one now looks at another substrate, e.g., Methimazole, the impact of the variants may be quantitatively different, e.g., the same variant that reduces TMA oxidation by 80% may only reduce Methimazole oxidation by 50%.

In the case of a heterozygote for the above examples, wherein one allele is “normal” and the other allele encodes the variant, the impact will be a combination of both with 50% of the phenotype being contributed by one allele and 50% by the other. In the case of the allele reducing function by 80%, the heterozygote’s phenotype would be a 40% reduction in overall capacity to oxidize TMA and for the individual heterozygote with a single copy of the 20% loss, only a 10% reduction in metabolic capacity. Thus, you can see that one individual may be more at risk from a challenge than another, depending on the variant.

The other database that I am not sure anyone has looked at yet for FMO3 is the whole exome sequence database. This is being done at the University of Washington, but they have sequenced the whole exome on some 2000 Caucasians and 1000 African Americans and have the results in a database anyone can query for their favorite gene. They also report whether or not the variant identified is common or rare and whether or not the variants is for a conserved amino acid and might have an important function.

Following the information Dr Hines gave about the exome database held by the University of Washington, we managed to find the database online and searched FMO3. Here is the database if you wish to search it. It is quite technical. SNP's are single nucleotide polymorphisms; missense mutations that are more than 1% in the population (the most common form of genetic fault; usually either detrimental, benign, but it can be an improvement).

NHLBI Exome Sequencing Project : Search of FMO3 enzyme