CBS and MTHFR Made Simple

Reader takeaway:  The CBS gene does not automatically lead to sulphur sensitivity or overuse of methyl groups, and CBS and MTHFR variances dovetail to clear homocysteine.

If you've explored your methylation genetics, you may have encountered a gene called CBS, or cystathionine beta-synthase. CBS often appears alongside MTHFR on genetic reports, and online interpretations can sound alarming. You may read that a CBS variant causes the pathway to run “too fast,” depletes methyl groups, creates too much ammonia or sulfur, and means you should avoid sulfur-rich foods.

The actual science is considerably more nuanced. CBS is unquestionably important to methylation and homocysteine metabolism. However, having a common CBS variant is very different from having CBS deficiency, and many of the symptoms attributed to common CBS SNPs have not been demonstrated in clinical studies, although they may be experienced by people with the CBS gene variance under conditions of nutritional stress. Understanding that distinction can make genetic information much more useful.

Having CBS and MTHFR don't automatically mean you need to avoid eggs, although this man might want to after posing for this picture.

What Does CBS Actually Do?

Homocysteine sits at an important metabolic crossroads. It can be recycled back into methionine through the remethylation pathway, which depends on folate, vitamin B12 and, indirectly, MTHFR. Or homocysteine can leave the methionine cycle through the transsulfuration pathway.

CBS controls the first major step of transsulfuration, combining homocysteine with serine to form cystathionine. Cystathionine can subsequently contribute to production of cysteine and downstream sulfur compounds most notably, glutathione. CBS requires pyridoxal-5'-phosphate, the active form of vitamin B6, as a cofactor. CBS is also regulated by S-adenosylmethionine, or SAM, our major cellular methyl donor. Structural studies of the human enzyme show that SAM binds to CBS and activates it.

This is an elegant feedback system: when methionine and SAM availability are relatively abundant, CBS can help direct homocysteine away from remethylation and toward transsulfuration. In other words, CBS isn't separate from methylation. It helps regulate the traffic flowing through it.

CBS and MTHFR: Two Sides of the Homocysteine Crossroads

This is where the relationship with MTHFR becomes particularly interesting. MTHFR helps generate 5-methyltetrahydrofolate, which provides the methyl group needed to recycle homocysteine back into methionine. The common MTHFR C677T variant, or the compound heterozygous variants, can reduce enzyme activity, particularly in the TT genotype and when folate status is low.

CBS pushes homocysteine in the opposite direction, out of the methionine cycle and into transsulfuration. This means that reduced activity in both pathways could make it more difficult to clear homocysteine.

Sadly, common genetic variants don't always behave the way a pathway diagram predicts.

One fascinating human study looked at the CBS 844ins68 variant together with MTHFR C677T. Among men with the MTHFR 677TT genotype, carriers of CBS 844ins68 actually had homocysteine concentrations about 24% lower than non-carriers and higher serum folate. The researchers suggested that this CBS variant might partially compensate for the MTHFR-related biochemical phenotype. So gene-gene interactions can sometimes be unexpectedly protective rather than additive.

What About the Infamous CBS C699T Variant?

One of the most commonly discussed CBS SNPs in methylation circles is C699T, also called rs234706. Importantly, C699T is a synonymous variant: it does not change the amino acid encoded at that position in the CBS protein. A study involving more than 1,000 people found that carriers of the 699T allele had somewhat lower homocysteine after a methionine load. The investigators speculated that C699T could be linked to nearby regulatory DNA that increases CBS expression.

Notice the difference between that finding and the claim often made online. The study did not demonstrate that everyone with C699T has pathologically overactive CBS. It did not demonstrate sulfur intolerance, excessive ammonia production or a characteristic symptom pattern. The proposed increase in transcription was a hypothesis based on the homocysteine findings.

Similarly, studies of the relatively common CBS 844ins68 insertion have produced modest and sometimes conflicting findings. One study concluded that it was essentially a neutral polymorphism with respect to hyperhomocysteinemia, while another found somewhat lower post-methionine homocysteine among carriers.

When CBS Mutations Matter

There is, however, another category of CBS variants that matters enormously. Rare pathogenic mutations affecting both copies of the CBS gene can cause classical homocystinuria, an autosomal-recessive metabolic disorder in which CBS activity is substantially impaired.

This is not the same as carrying C699T on a consumer genetic test. In CBS deficiency, homocysteine can become dramatically elevated. Methionine is often elevated as well, while cysteine may be reduced. A large European registry study involving 328 people with CBS deficiency documented a broad spectrum of disease, from developmental problems and lens dislocation in childhood to adults whose first major presentation was thromboembolism.

Possible manifestations include:

• dislocation of the lens of the eye,

• severe myopia,

• tall or Marfan-like skeletal features,

• osteoporosis,

• developmental or cognitive difficulties,

• psychiatric or neurologic symptoms,

• and blood clots, including venous and arterial thrombosis.

Thromboembolism is particularly important. In one multicenter series, vascular complications occurred in roughly one-third of patients with homocystinuria, especially in untreated or late-diagnosed individuals. These risks apply to classical CBS deficiency (an actual metabolic disease) , not automatically to common CBS SNPs.

Could CBS Affect Methylation?

Potentially, yes, but not in the simplistic sense of being either “overmethylated” or “undermethylated.” Methylation depends partly on the balance between SAM and S-adenosylhomocysteine (SAH). After SAM donates a methyl group, SAH is produced. Homocysteine metabolism helps keep that system moving.

If homocysteine becomes severely elevated because CBS activity is deficient, associated disturbances in one-carbon metabolism can potentially affect methylation chemistry as well.

At the same time, SAM itself activates CBS. This means methylation and transsulfuration regulate one another rather than functioning as isolated pathways. That is why a single SNP generally cannot tell us whether someone's overall methylation is “fast” or “slow.”

What Symptoms Might Someone With a Common CBS Variant Notice?

This is an area where caution is especially important. People online sometimes associate CBS variants with:

• fatigue,

• headaches,

• anxiety,

• brain fog,

• difficulty tolerating sulfur foods,

• sensitivity to supplements,

• unusual body odor,

• insomnia,

• or reactions to methyl donors.

These experiences may certainly be real, but whether or not they're coming from common CBS variants such as C699T is not actually clear. If a CBS variant is concerning, homocysteine, nutrient status and other metabolic markers provide much more useful information than assuming that a SNP is causing symptoms.

What Can You Do at Home For CBS?

If your genetic report shows a common CBS variant, the first step is surprisingly simple:

Don't panic, and don't immediately restrict sulfur. Foods such as eggs, meat, fish, legumes, broccoli, Brussels sprouts, onions and garlic provide important amino acids and sulfur-containing compounds. There is no good evidence that everyone carrying common CBS polymorphisms needs a low-sulfur or low-protein diet. Instead, think in terms of supporting the entire pathway.

Eat a varied diet that provides adequate:

• folate,

• vitamin B12,

• vitamin B6,

• riboflavin,

• choline,

• betaine,

• protein,

• magnesium,

• and colorful plant foods.

If you're taking a complicated methylation supplement regimen, introduce changes gradually rather than adding methylfolate, methyl-B12, SAMe, TMG and multiple B-complex products simultaneously. Also, use a combination of symtpom tracker and common blood tests that help indicate nutritional status and methylation status to determine what your body actualy needs.

One caution: don't use large doses of vitamin B6 or prescription-level betaine simply because a consumer genetic test reports a CBS SNP. In true CBS deficiency, pyridoxine responsiveness varies greatly between individuals, and treatments such as pharmacologic B6, betaine and methionine restriction are used under metabolic-specialist supervision.

Treat the Pathway, Not the SNP

CBS is a fascinating gene precisely because it demonstrates why methylation cannot be reduced to a collection of red and green boxes on a genetic report. MTHFR helps determine how efficiently homocysteine can return to methionine. CBS helps determine how efficiently it can enter transsulfuration. SAM helps regulate CBS itself, and vitamin B6 affects CBS enzyme function.

Folate and B12 influence the competing remethylation pathway. And common genetic variants may change these processes slightly, dramatically, or sometimes hardly at all. Not complicated at all, right?

References

Kraus JP, Le K, Swaroop M, et al. Human cystathionine beta-synthase cDNA: sequence, alternative splicing and expression in cultured cells. Hum Mol Genet. 1993;2(10):1633-1638. doi:10.1093/hmg/2.10.1633. PMID: 7903580.

McCorvie TJ, Kopec J, Hyung SJ, et al. Inter-domain communication of human cystathionine β-synthase: structural basis of S-adenosyl-L-methionine activation. J Biol Chem. 2014;289(52):36018-36030. doi:10.1074/jbc.M114.610782. PMID: 25336647.

Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111-113. doi:10.1038/ng0595-111. PMID: 7647779.

Summers CM, Hammons AL, Mitchell LE, et al. Influence of the cystathionine beta-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations. Eur J Hum Genet. 2008;16(8):1010-1013. doi:10.1038/ejhg.2008.69. PMID: 18398434.

Aras O, Hanson NQ, Yang F, Tsai MY. Influence of 699C→T and 1080C→T polymorphisms of the cystathionine beta-synthase gene on plasma homocysteine levels. Clin Genet. 2000;58(6):455-459. doi:10.1034/j.1399-0004.2000.580605.x. PMID: 11149614.

Kluijtmans LAJ, Boers GHJ, Trijbels FJM, van Lith-Zanders HM, van den Heuvel LP, Blom HJ. A common 844INS68 insertion variant in the cystathionine beta-synthase gene. Biochem Mol Med. 1997;62(1):23-25. doi:10.1006/bmme.1997.2623. PMID: 9367794.

Tsai MY, Yang F, Bignell M, Aras O, Hanson NQ. Relation between plasma homocysteine concentration, the 844ins68 variant of the cystathionine beta-synthase gene, and pyridoxal-5'-phosphate concentration. Mol Genet Metab. 1999;67(4):352-356. doi:10.1006/mgme.1999.2874. PMID: 10444346.

Kožich V, Sokolová J, Morris AAM, et al. Cystathionine β-synthase deficiency in the E-HOD registry—part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis. J Inherit Metab Dis. 2021;44(3):677-692. doi:10.1002/jimd.12338. PMID: 33295057.

Simorre B, Quéré I, Berrut G, et al. Vascular complications of homocystinuria: a retrospective multicenter study. Rev Med Interne. 2002;23(3):267-272. doi:10.1016/S0248-8663(01)00551-3. PMID: 11928374.

Singh RH, Kruger WD, Wang L, Pasquali M, Elsas LJ II. Cystathionine beta-synthase deficiency: effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria. Genet Med. 2004;6(2):90-95. doi:10.1097/01.GIM.0000117334.84388.F4. PMID: 15017331.