⏰ A Short Introduction! TL;DR
Let me first give you a short introduction to this blog post and what you can expect from it.
The post is focused on the MTHFR gene, and the content of this post covers the following topics related to the MTHFR gene :
1️⃣ The basic information about the MTHFR gene and the function of the enzyme it encodes.
2️⃣ The two main genetic variants (mutations) being associated with MTHFR deficiency:
rs1801131, also known as C677T, and
rs1801133, also known as A1286C
3️⃣ Instructions (Including VIDEO TUTORIAL) on interpreting genotype results for the two genetic variants/mutations mentioned above. Also, if you have 23andMe data, you can extract that information using Figure 2 and the already-mentioned video tutorial.
📒 MTHFR Gene: What does it encode? What is the function of MTHFR? An Some Other Stuff
🧑🏽🚀 Discovery: The MTHFR gene was discovered in 1988 by Kang et al. [citation], and the discovery happened due to the performance of enzymatic assays of lymphocyte extracts in patients with cardiovascular disease.
🗺️ Location: The human MTHFR gene is located on chromosome 1, roughly 20241 bases long. According to the ENSEMBL database, the MTHFR gene has 19 transcripts (splice variants), 205 orthologues, and four paralogues and is associated with 21 phenotypes.
🧫MTHFR Function (Complex): The MTHFR gene encodes an enzyme called methylenetetrahydrofolate reductase (MTHFR). In the blog post, when I refer to MTHFR, I mean the enzyme methylenetetrahydrofolate reductase, and if I want to refer to the gene, I will write the MTHFR gene.
As I already wrote, MTHFR stands for methylenetetrahydrofolate reductase. It catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The 5-methyltetrahydrofolate serves as a co-substrate for the conversion of homocysteine into methionine.
More precisely, this process is called methylation of homocysteine into methionine. So, MTHFR (methylenetetrahydrofolate reductase) is one of the critical elements in the pathway for rate limitation in the methyl cycle.
Now, this probably does not tell you much; if it does, you probably already know everything about MTHFR, and you can jump directly to the section about the MTHFR gene mutations, but if this is not the case, let me simplify what I just wrote above.
Figure 1: Function of MTHFR
🧫MTHFR Function (Simplified): Let’s try to follow the illustration above (Figure 1). First, we intake vitamin B9 through food. The other name for vitamin B9 is folate. Folate is processed in the form of 5,10-methylenetetrahydrofolate and converted into 5-methyltetrahydrofolate. The 5-methyltetrahydrofolate is further used in DNA synthesis or participates in the conversion of homocysteine into methionine, as illustrated in the above figure. Homocysteine and methionine are amino acids, and amino acids serve as building blocks for protein.
ℹ️ Methionine is essential amino acid in protein synthesis and the processes of cellular methylation. On the other side, tetrahydrofolate, a version of vitamin B9, has an important role in DNA synthesis.
📝 MTHFR Function (final): Finally, from what I wrote, one can quickly figure out that if there is any function defect in the MTHFR enzyme, it can lead to:
Decreased production of 5-methyltetrahydrofolate which will decrease the conversion of homocysteine into methionine, which will further lead to the accumulation of homocysteine and not enough methionine.
This is a consequence of having less functional MTHFR, but I will write more about that in the following sections.
🧬 The MTHFR Gene’s Mutations
ℹ️ In the previous section, I briefly introduced the MTHFR gene and explained the function of the MTHFR enzyme. The following sections of the post will provide you with an overview of the two most important genetic variants related to the MTHFR deficiency.
🧬Like any other gene, the MTHFR gene can have mutations that eventually can lead to changes in the functionality of the MTHFR enzyme it encodes.
🧬Mutations affecting the functionality of the MTHFR enzyme can lead to an accumulation of homocysteine in the blood and potentially lead to health problems such as an increased risk of cardiovascular disease and birth defects.
ℹ️ Refer to Figure 1 and the explanation of the MTHFR function in the previous section on how this accumulation of homocysteine can happen.
ℹ️ However, it's important to note that having an MTHFR mutation does not necessarily mean a person will develop these health problems.
🧬 The MTHFR Gene's Mutations: C677T (rs1801133) and A1298C (rs1801131)
In this blog post, I will focus on the two most essential mutations in the case of the MTHFR gene, and those are:
🧬C677T (rs1801133, C665T) is a genetic variant representing a C to T mutation at mRNA position 677 that changes from alanine to valine at protein position 222. This genetic variant is known as Ala222Val and A222V, besides going under the name of C677T and rs1801133. I want to underline that C677T is the historical name, and the more accurate would be C665T. But throughout this blog post, I will stick to C677T and rs1801133, which are still more common.
🧬A1298C (rs1801131, A1286C) is a genetic variant representing an A to C mutation at mRNA position 1298 that changes from glutamic acid to alanine at protein position 429. This genetic variant is also known as Glu429Ala and E429A, besides going under the name of A1298C or rs1801133. Similarly, like in the case of C677T, here also, the more accurate name should be A1286C instead of A1298C, which is the historical name. But throughout this blog post, I will stick to A1298C and rs1801131, which are still more common.
📊How Common Are C677T (rs1801133) and A1298C ( rs1801131) MTHFR Mutations?
📊According to 1000 Genomes Project data, the global allele frequency for the T allele of C677T (rs1801133) is 25%, with the highest frequency in populations of European origin being 36% and the lowest allele frequency in the African population being 9%.
📊In the case of A1298C (A1286C, rs1801131) mutation, the global allele frequency for the C allele is A1298C (A1286C, rs1801131) is also 25%, with the highest frequency in the South Asian population at 42%, and the lowest allele frequency in the African and Native American populations being 15%.
ℹ️ How To Interpret the Results of MTHFR Gene’s Mutations
⚠️ It is important to note that if there is a suspicion of MTHFR deficiency, it is the standard procedure to measure the levels of homocysteine and combine this information with the results of MTHFR gene testing.
ℹ️ Individuals who are “MTHFR positive” carry one or two copies of variants in the MTHFR gene, and to get the complete picture of how to interpret the MTHFR gene testing results, please check the illustration below (Figure 2). I also created a short video tutorial that you can check below.
Video Tutorial on Interpreting MTHFR mutation
📝 Interpreting The Functional Effects Of MTHFR Gene's Mutations
⚠️ Please refer to Figure 2 and/or video tutorial for interpretation of your genotype results for C677T (rs1801133) and A1298C (rs1801131).
MTHFR C677T: MTHFR C677T means a point mutation at base position 677, due to which cytosine is substituted with thymine and amino acid alanine is converted to valine in the enzyme. If you are TT homozygous for C677T, it means that you are MTHFR-positive and that if you have increased levels of homocysteine, those are associated with the MTHFR deficiency.
MTHFR C677T: Being positive for one copy of the C677T mutation means that the person has one copy of the MTHFR gene mutated in a way that there is thymine instead of cytosine at the specific locus (genotype CT) as explained above. Heterozygosity at this locus leads to a 35% reduction of enzyme function [citation] and probably does not lead to any clinical consequences. However, suppose one is positive for one copy of C677T (genotype CT) and one copy of A1298C (genotype AC) in this situation. In that case, the genetic test result will be considered MTHFR positive.
MTHFR A1298C: MTHFR A1298C heterozygous means that one of the copies of MTHFR has a point mutation at position 1298, where adenine is substituted by cytosine. Hence amino acid glutamate is substituted by alanine in the enzyme product.
MTHFR A1298C: Being positive for one copy of the A1298C variant means the person has one copy of the mutated gene (heterozygous or AC genotype). Heterozygosity leads to no changes to the protein [citation], but it is crucial to have genotype information for C677T. In this case, C677T mustn't be TT homozygous.
MTHFR A1298C: If you are CC homozygous for the A1298C mutation, you will be considered MTHFR-positive, but unlikely to have any clinical problems related to the MTHFR deficiency. However, it is essential to say that you should not be TT homozygous for C677T, and if you are TT homozygous for C677T, then you are considered MTHFR-positive. If you have increased levels of homocysteine, it is associated with MTHFR deficiency.
👩🏻⚕️ MTHFR Gene’s Mutations & Disease Risk
⚠️ It is advised and essential for all individuals to determine whether medical disorders have been wrongly associated with their positive MTHFR status. So, please refer to a hematologist or maternal–fetal medicine specialist for detailed consultations. Also, patients should provide their MTHFR genotype results to their physician before starting chemotherapy agents that require folate.
⚕️Venous thrombosis or recurrent pregnancy loss: According to the most recent evidence, if you are TT homozygous for C677T with normal homocysteine levels, you do not have an increased risk of venous thrombosis or recurrent pregnancy loss. However, women have a modestly increased risk of having a child with a neural tube defect, which increases if the fetus is also homozygous. If homocysteine levels are elevated, TT homozygotes may have a mildly increased risk of venous thrombosis or recurrent pregnancy loss but not other previously associated conditions, such as cardiovascular disease.
ℹ️ We know less about the A1298C mutation, but current evidence tells us that it has a milder effect in comparison to the C677T mutation.
💊 Finally, individuals having MTHFR-positive results may decide to take vitamin B and folic acid supplements. Although safe (toxicity is rare), evidence is lacking on whether such supplements reduce the risks associated with hyperhomocysteinemia or MTHFR genotype status.
👩🏽⚕️ MTHFR Gene’s Mutations & Hyperhomocysteinemia
Having a functional MTHFR gene means that the body can convert homocysteine to methionine while having a mutated MTHFR gene indicates susceptibility to hyperhomocysteinemia. Hyperhomocysteinemia is a condition that is characterized by the buildup of homocysteine in the plasma [citation]. Homocysteine is accumulated due to methylenetetrahydrofolate reductase (MTHFR) deficiency.
Being TT homozygous for C677T or heterozygous for both C677T and A1298C leads to MTHFR deficiency manifested in hyperhomocysteinemia. Hyperhomocysteinemia is a condition where the body cannot process homocysteine and convert it to methionine properly, thus leading to homocysteine build-up plasma that further leads to other metabolic problems manifested through eye problems, abnormal blood clotting, skeletal abnormalities, and learning problems [citation].
🧪 How Are You Tested for the MTHFR Gene Mutations?
The physician first determines the necessity for MTHFR gene testing by reviewing the medical history in the context of current symptoms.
The first step is to test homocysteine levels, and if homocysteine levels are elevated, the MTHFR gene testing is advised. Next, the MTHFR genetic test looks for the two common mutations I already presented in the previous sections (C677T and A1298C).
💰 How Much Does an MTHFR Test Cost?
🧬 Where Is the MTHFR Gene on 23andMe?
Both A1298C (rs1801131) and C677T (rs1801133) can be found in the raw genotype files from 23andMe.
So, if you performed the 23andMe genetic test and would like help with this, send me an email (you can do it via the Contact form on www.biocomputix.com), and I will give you instructions on how to extract genotype information and how to interpret it.
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