New member & FMO3 discoverer

[FADworker]

Hi

First, congratulations on setting up an impressive self-help site that I have been following for some time. It certainly provides a fantastic forum for TMAU patients and their friends and family to discuss TMAU-related issues. I'm Colin Dolphin and was part of the team who first demonstrated that mutations in the FMO3 gene are the cause of the inherited (primary form) of TMAU. I haven't registered here (or indeed on any of the other TMAU forums) before now because, as a non-clinical scientist, I felt it would be inappropriate for me to answer medical type questions. However, if you woulld like to know more about the basic science surrounding the FMO3 gene, the enzyme (also simply called FMO3) that it codes for and their relationship to TMAU I would be happy to try and help.

[flower]

I have a question :

If we are genetic tested for tmau (FMO3-gen), are we also tested for nonsense mutations ?
I read that there is known to be a nonsense mutation possible at amino acid 148. Just read it today on another site.

Thanks for giving us some explenation about the FMO 3-gen.

Flower

[FADworker]

I have a question :

If we are genetic tested for tmau (FMO3-gen), are we also tested for nonsense mutations ?
I read that there is known to be a nonsense mutation possible at amino acid 148. Just read it today on another site.

Thanks for giving us some explenation about the FMO 3-gen.

Flower

Hi flower

Yes there is a mutation in the gene that corresponds to amino acid position 148. This changes the code so that rather than placing the amino acid glycine at that position in the protein chain the chain growth is stopped - the definition of a nonsense mutation. You would most likely be tested for this but I can't be sure. HTH.

[PoetFire]

Hi Colin. Thanks for posting. It is a privilege and we are most grateful to you for taking the time to communicate with us. At this stage in the history of TMAU we are better off talking direct with the researchers. Most Drs still haven't heard of it. I noticed your name in early FMO3 genetic papers. Do you still work on FMO3 research ? I guess genetics rather than FMO3 itself is what your work is based around ?

A couple of questions I had were :

What % of the population do you think is potentially 'at risk' of genetic TMAU (of some sort) when you include those who don't have obvious severe mutations ? There was a paper by Dr Cashman where some ladies who were carriers of common variants could dip in FMO3 function at menstruation. I wondered if some considered 'carriers' could in fact be at risk of TMAU 'incidents' etc. Do you think 1% is too high an estimate ?

Also, Mallory is rallying the troops to try and raise awareness amongst the population and politicians to get research going. Would you have any advice as to how we should go about getting research going or any other suggestions how we can get society to do something about genetic TMAU ?

[FADworker]

Hi Colin. Thanks for posting. It is a privilege and we are most grateful to you for taking the time to communicate with us. At this stage in the history of TMAU we are better off talking direct with the researchers. Most Drs still haven't heard of it. I noticed your name in early FMO3 genetic papers. Do you still work on FMO3 research ? I guess genetics rather than FMO3 itself is what your work is based around ?

A couple of questions I had were :

What % of the population do you think is potentially 'at risk' of genetic TMAU (of some sort) when you include those who don't have obvious severe mutations ? There was a paper by Dr Cashman where some ladies who were carriers of common variants could dip in FMO3 function at menstruation. I wondered if some considered 'carriers' could in fact be at risk of TMAU 'incidents' etc. Do you think 1% is too high an estimate ?

Also, Mallory is rallying the troops to try and raise awareness amongst the population and politicians to get research going. Would you have any advice as to how we should go about getting research going or any other suggestions how we can get society to do something about genetic TMAU ?

Thanks for the welcome. Working on FMO3 at that time was very exciting particularly as there was a significant element of (healthy) competition driving us on - 7-day weeks were the norm. My research has migrated into different areas since then but I've always been interested in how the field has moved forward. With the creation of this UK site I thought I'd offer support and answer questions where I can.

As to your questions: as you know primary TMAU occurs when two 'inactive' FMO3 genes are present that results in no FMO3 enzyme function and thus no TMA oxidation capacity in the liver. As well as these so-called loss-of-function forms of the FMO3 gene there are other forms which code for an FMO3 enzyme that has a reduced ability to oxidise TMA. These forms are called decreased-function forms. An individual who has inherited one loss-of-function FMO3 form and a 'normal' one (a heterozygote) will have a reduced amount of functional FMO3 enzyme and thus may occasionally have problems in oxidising TMA especially if they have eaten something that leads to the production of a large amount of TMA in the gut and/or their already reduced FMO3 capacity is further lowered which can you happen, as you say, at menstruation. The same situation can occur for individuals inheriting either loss-of-function and decreased-function forms of even two decreased-function forms. So TMAU can be viewed as more of a spectrum of odour severity, sometimes occasional, depending on the FMO3 forms inherited and other factors such as dietary load of TMA precursors. As to how common these cases are is difficult to tell but probably more common that we think.

As to further raising the profile of the condition forums such as this do a great job and help make more dietary advice and councelling available which wasn't before. I've seen the idea of emailing MPs, etc and that must be a good way of lobbying for further support.

HTH

[kittycat]

Hello Mr Dolphin, yes, thank you very much for giving your time to answer our questions.
I don't know if this question is in your remit, but even a speculation would be interesting...Is it possible to manufacture the FMO3 enzyme, and would it help Tmau, primary or aquired? Regards, kittycatx

[FADworker]

Hello Mr Dolphin, yes, thank you very much for giving your time to answer our questions.
I don't know if this question is in your remit, but even a speculation would be interesting...Is it possible to manufacture the FMO3 enzyme, and would it help Tmau, primary or aquired? Regards, kittycatx

Hi kittycat,

The enzyme can indeed be 'manufactured' - its a protein and most proteins can be made in the lab' using a 'host' animal (or plant) to make it for us. This host is usually a lab' strain of E. coli or we can use yeast or cultures of cells. However, the FMO3 enzyme would need to be introduced into the liver - which is the major site in the body for the oxidation of TMA - and this would not be possible for a protein. That said the alternative would be to introduce a 'normal' copy of the FMO3 gene into a patient's liver and then the gene would direct the liver cells to produce FMO3 enzyme in the correct location. This is 'gene therapy' and, although its been around for 30 years or more, its had really very little success for any inherited disease. In theory gene therapy would help in TMAU - in practice the technological hurdles that still have to be overcome for any form of gene therapy are still pretty formidable.

[ashapiro]

Good afternoon. I work as a science reporter for a BBC World Service program in the US called "The World," and I'm exploring a story on TMAU. I am hoping to make a trip to the UK next week to record some interview material, and I thought I would try posting to this forum.

I would like to interview someone with the genetic condition (Type 1 TMAU) who would be willing to share their story with me. Ideally, I'd like to speak with someone who lived with the condition for a while before knowing it was genetic, and subsequently found out that it was genetic. I'm curious about how that's impacted them.

Yours sincerely,
ari daniel shapiro

aridanielshapiro@gmail.com
www.aridanielshapiro.com