DIO1 and DIO2 Gene Defects and Testing Them

The D1 and D2 deiodinase enzymes are produced in our cells to enable the conversion of FT4 to FT3 to occur within our cells. Both enzymes are seleno-proteins, i.e. they have selenium as part of their structure. Hence, if someone has low levels of selenium this can hamper conversion. Many thyroid patients take 100 or 200 mcg of selenium supplement per day to ensure they have sufficient.

The higher the number of these enzymes produced the higher the conversion rate. TSH also has an impact, if TSH goes up the D1 and D2 enzymes are upregulated, i.e. more are produced in each cell, and conversion rate of T4 to T3 rises. If TSH goes down, the D1 and D2 enyzymes are downregulated, i.e. fewer are produced and coversion rate lowers (but there is still some conversion occurring).

However, some thyroid patients have gene defects that mean the quality of the D1 or D2 (or both) enzymes can be impaired. The mutations are referred to as DIO1 and DIO2. It is possible to have a bad copy of the mutation from one parent and a good copy from the other parent, in this case you would be heterozygous for the gene defect. If you have a bad copy from both parents, you are homozygous for the gene defect - which is worse as the quality of the deiodinase enzyme is liable to be worse.

Note: I have heard from one patient whose endocrinologist told her that there is no point in testing these, as if she had them she wouldn't convert T4 to T3 at all (she is very unwell on T4 medication). This is obviously rubbish. The gene defects, even if present with both copies of each DIO1 and DIO2 mutation,  impair the quality of the D1 and D2 enzymes, they do not stop them working totally. It just makes conversion worse - it doesn't totally stop it.

The DIO1 and DIO2 mutations do not always cause obvious conversion problems either. Some people are better at compensating for the defects than others. Geneticists do not fully understand this yet. However, it is this compensation that tends to make the mutations not affect people until late twenties/early thirties. Perhaps, a higher TSH might help compensate, as more deiodinase enzymes would be produced - but I am speculating. One thing is true though, if you have a mutation, it is there genetically in your make-up. It cannot be turned off or removed. It will in some way affect the ability of your cells to make good D1 and D2 enzymes. Over the next ten years more on all of this will no doubt be discovered.

The DIO1 and DIO2 genetic mutation tests are very useful to do, even if you have to do them privately. Knowing that you have one or both mutations (and whether you have them from one or both parents), will inform you of the potential risk of conversion issues. Both mutations can reduce T4 to T3 conversion, lowering FT3 and raising rT3, thus increasing the chances of on-going hypothyroidism. Having the mutation from both parents make the problem worse, but even from one it can have an effect.

The DIO1 mutation may affect conversion by the thyroid, liver and kidneys.

The DIO2 mutation may affect conversion by the brain, pituitary, central nervous system, thyroid, heart and peripheral tissues (skeletal muscle). Thus, the DIO2 mutation can also cause hypocortisolism, through the impact on the pituitary, i.e. due to HP dysfunction leading to lower ACTH. Note: once you have totally cleared T4 and are reliant on only T3, this conversion issue becomes unimportant, unless it has caused HP dysfunction that is slow to correct.

Although, the D1 deiodinase enzyme is less efficient in converting T4 to T3, it is still significant. It also is important in the liver as it involved in the clearance of rT3; so testing for the DIO1 mutation is helpful.

If you do a full genome mapping, please make sure the company offers both  DIO1 and DIO2 in their raw data.

How to Interepet the Results

If you've used  a company that do the single DIO1 and DIO2 tests, the results will be obvious in their report.

If you've used a company that does a full genome mapping, you have two choices:

1. Just use the Raw data.

The company may have a raw data browser, or you can look/search through the  raw data text file if needed.

DIO1 is referred to as "rs11206244". The normal allele (no defect) is 'C'. The 'T' allele is the mutation; it reduces T4 to T3 conversion, and raises rT3 when active.

DIO2 is referred to as "rs225014". The normal/wild-type allele (no defect) is 'T'. The 'C' allele is the mutation; it reduces T4 to T3 conversion, and raises rT3 when active. (Note: Some labs may use 'A' as the notation for the mutation - but this is not the standard nomenclature).

As briefly mentioned earlier, the results of testing show both copies of the gene - one from the person's mother and one from the person's father. If both allele's show no defect, there is no mutation at all. If one of them is a mutation, the person is said to be heterozygous for the defect, i.e. they have one copy. This is likely to impair the quality of the deiodinase enzymes (but not definitely). If both allele's have the mutation, the person is said to be homozygous for the defect and the chance of the deiodinase enzymes being impaired is higher and the consequence can be more severe.

So, for instance if you were looking for DIO2, you would search for 'rs225014' then look at the results there. 'TT' would mean you had no defect inherited from either parent. 'TC' or 'CT' would mean one parent gave you the defect and one did not (you are heterozygous for the defect). 'CC' would mean that you have both defective genes (you are homozygous, but as mentioned some labs may use 'A' instead of 'C').

For DIO1 you would search for  "rs11206244". 'CC' implies there are no inherited defects. 'CT' or 'TC' means you are heterozygous for DIO1. 'TT' means you are homozygous for the DIO1 mutation (you have both copies). 

2. Use a special filtering program.

Companies like 'Genetic Lifehacks' and 'Genetic Genie' offer software that read your genome mapping raw data and give you easier analysis of it.

Personally, I think the raw data is easy enough to look through.

Laboratories that Do the Testing

Regenerus Labs in the UK have a single test for DIO2 (the most important of the two mutations). They also deal with international customers, i.e. USA, rest of Europe:
Regenerus insist that you also pay for a counsellor to give you the result, however, you can try telling them that I know a huge about this area, have written three books on it and am acting as your practitioner - this may be good enough to avoid this extra charge.

Blue Horizon Medicals in the UK have a genetic profile test that includes the DIO1 and DIO2 raw data:  

23andMe only offers DIO1 in their raw data now. Just search for 23andMe and select the Ancestry option.

In July 2018 Ancestry (.co.uk and .com) still had both DIO1 and DIO2 in the raw data, and they operate in many countries including the USA and UK:

Nutrition Genome in the USA had both DIO1 and DIO2 in their raw data in August 2018. But this site only appears to work if you are in the USA.

Fulgent Genetics in the USA also provide DIO1 and DIO2 test results:

I hope you found this useful. I do believe that the DIO1 and DIO2 tests are useful to do, especially if you can see in your thyroid lab results that you are having poor conversion issues. The presence of one or both of these mutations would at least provide a concrete explanation for why this might be and hopefully persuade your physician to switch the balance of your thyroid medication to more T3 and less T4. Loss of thyroid tissue also loses conversion rate remember though - so this can be another reason for issues. I discuss all of these types of problems in my latest book, 'The Thyroid Patient's Manual'

I am sure over time more gene defects will be discovered that affect thyroid hormone uptake into cells, the binding to thyroid receptors and much, much more.

Best wishes,