A1298C Variant

A1298C – a mutation from adenine to cytosine at position 1298 within the gene. These variants lead to amino acid differences in the protein that reduces its ability to function.

1298:genes_MTHFR_baucom_institute

  • AA-normal homozygous
  • AC or CC – one or two variant copies
  • about 30% of the population
  • not associated with increased risk
  • associated with increased risk if found together with a 677 variant

Severe MTHFR deficiency:

  • Severe MTHFR deficiency is rare (about 50 cases worldwide) and caused by mutations resulting in 0-20% residual enzyme activity.
  • Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria. Hum Mutat 15 (3): 280-7
  • These patients exhibit:
  1. developmental delay,
  2. motor and gait dysfunction,
  3. seizures,
  4. neurological impairment and
  5. have extremely high levels of homocysteine in their plasma and urine as well as low to normal plasma methionine levels.

Epigenetic_mechanisms_MTHFR_methylationBottom line:  If one leads a lifestyle which is unhealthy (smoking, high stress, toxic exposures) and consumes an unhealthy diet (refined carbs, processed meats, saturated fats), having a heterozygous A1298C mutation may contribute to cardiovascular disease, depression, fibromyalgia and others.

Possible symptoms associated with A1298C MTHFR mutations:

  • hypertension
  • delayed speech
  • muscle pain
  • insomnia
  • irritable bowel syndrome
  • fibromyalgia
  • chronic fatigue syndrome
  • hand tremor
  • memory loss
  • headaches
  • brain fog

Possible signs associated with A1298C MTHFR Mutations:

  • elevated ammonia levels
  • decreased dopamine
  • decrease serotonin
  • decreased epinephrine and norepinephrine
  • decreased nitric oxide
  • elevated blood pressure
  • muscle tenderness
  • ulcers
  • pre-eclampsia

Possible conditions associated with A1298C MTHFR mutations:

  • fibromyalgia
  • chronic fatigue syndrome
  • autism
  • depression
  • insomnia
  • ADD/ADHD
  • irritable bowel syndrome
  • inflammatory bowel syndrome
  • erectile dysfunction
  • migraine
  • Raynaud’s
  • cancer
  • Alzheimer’s
  • Parkinson’s
  • recurrent miscarriages

Frequency of MTHFR Polymorphisms

30-40% of Americans are found to have either a single or double polymorphism of either C677T or A1298C.

  • There is ethnic variability in the frequency of the T allel-frequency in Mediterranean/Hispanics>Caucasians>Africans/African-Americans (Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet 62 (5): 1258-60)
  • Higher frequency in chronic disease: Autoimmune diseases, diseases of the gut, Fibromyalgia, Chronic Fatigue, Chronic Retroviruses, Cancer, Hormone dysregulation, Mood issues, Cardiometabolic patients.

C667Tpolymorphtandem-baucom-institute

  • There is a mutation from cytosine to adenine at position 677 within the gene.
  • Possible genotypes?
  • 677-CC, CT, or TT
  • CC-homozygous normal
  • About 45% of the population
  • No increased risk associate
  • CT-on variant copy
  • About 45% of the population
  • Some reduced enzymatic activity, alone not associated with increased risk
  • TT-two variant copies
  • About 10% of the population
  • Increased risk for elevated homocysteine level and associated complications

Homocysteine & Vascular Disease

Pathophysiology of Homocysteine:

1. Interference with normal thrombolysisHomocysteine-Damage-Ladd-McNamara

  • decreased antithrombin III activity
  • Activation of factor V or XII
  • Inactivation of protein C
  • Promote binding of Lp(a) to fibrin
  • Platelet inhibition (interaction with nitric oxide)

2. Promote SMC proliferation

3. Promote LDL oxidation

4. Direct toxicity to endothelium

Genetic and Dietary Determinants of Serum Homocysteine Concentrations:

Genetic -

  • Cystathionine-beta-synthase deficiency
  • Methionine synthase deficiency
  • MTHFR deficiency
  • Defective absorption of B12 or folate
  • Prevalence – 30% Female V. 25% Male

lowering-homocysteine-levels-naturally-baucom-instituteNutritional -

  • Vitamin B6
  • Vitamin B12
  • Folate

Risks Associated with MTHFR Variants/High Homocysteine:

  • Cardiovascular Disease
  • Cerebral Vascular Disease (stroke)
  • Venous and Arterial Thrombosis
  • Methotrexate Toxicity for Cancer Therapy

 

Methylation

Methylation can turn genes on or off.

Some nutrients affect the methylation process quite dramatically. Methylating factors like B12, B6, MD, Zinc monitor specific methylation reactions.

Methylation_DNA_Baucom_InstituteMTHFR

What is MTHFR?

  • Methylenehydrofolatereductase is an enzyme responsible for converting 5, 10- methylenetetrahydrofolate to the product: 5-methytetrahydrofolate (5-MTHF)
  • Certain mutations in the gene coding for MTHFR produce an enzyme that has reduced activity
  • Reduced activity can lead to elevated levels of homocysteine especially when folate levels are low
  • MTHRF genotyping can provide information about potential causes of elevated homocysteine and how to address it
  • 5-methyltetrahydrofolate is involved in the metabolism of folate and homocysteine
  • The product of the reaction catalyzed by MTHFR converts homocysteine (a potentially toxic amino acid) to methionine (a useful and necessary amino acid)