Mthfr, or 5,10-Methylenetetrahydrofolate reductase, is a key enzyme in the folate metabolism pathway, which is integral for cell metabolism, especially in DNA, RNA, and protein methylation [1]. It is mapped on chromosome 1 at the end of the short arm (1p36.6). The enzyme is vital for maintaining methionine and homocysteine balance within cells, thus ensuring cellular homeostasis, and is involved in the one-carbon cycle, which includes methionine and folate metabolism and nucleic acid synthesis [2].

The Mthfr C677T polymorphism, located at exon 4, is associated with various diseases such as vascular diseases, cancers, neurological disorders, diabetes, psoriasis, and more [1]. This polymorphism results in an amino acid change from alanine to valine at codon 222, reducing the enzyme's activity. Homozygous mutated subjects have higher homocysteine levels, and heterozygous mutated subjects have mildly raised homocysteine levels compared to non-mutated controls [1]. Hyperhomocysteinemia is an emerging risk factor for cardiovascular diseases [1]. Additionally, Mthfr 1298A>C substitution shows an association with recurrent pregnancy loss in a population-specific manner, being a strong risk factor in Caucasian populations [3]. The C677T polymorphism of Mthfr has also been associated with an increased risk of rheumatoid arthritis, especially in African and Asian populations under certain genotype models [4], and with neural tube defects, particularly among Caucasians and Asians [5].

In conclusion, Mthfr is crucial for folate metabolism, methionine-homocysteine balance, and the one-carbon cycle, with significant implications for multiple biological processes and disease conditions. The study of Mthfr gene polymorphisms, especially C677T and 1298A>C, through genetic models can help understand its role in various diseases, providing potential insights for prevention and treatment strategies [1,2,3,4,5].

References:

1. Liew, Siaw-Cheok, Gupta, Esha Das. 2014. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. In European journal of medical genetics, 58, 1-10. doi:10.1016/j.ejmg.2014.10.004. https://pubmed.ncbi.nlm.nih.gov/25449138/

2. Raghubeer, Shanel, Matsha, Tandi E. 2021. Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks. In Nutrients, 13, . doi:10.3390/nu13124562. https://pubmed.ncbi.nlm.nih.gov/34960114/

3. Mehta, Poonam, Vishvkarma, Rahul, Singh, Kiran, Rajender, Singh. 2021. MTHFR 1298A>C Substitution is a Strong Candidate for Analysis in Recurrent Pregnancy Loss: Evidence from 14,289 Subjects. In Reproductive sciences (Thousand Oaks, Calif.), 29, 1039-1053. doi:10.1007/s43032-021-00530-5. https://pubmed.ncbi.nlm.nih.gov/33742421/

4. Bagheri-Hosseinabadi, Zahra, Imani, Danyal, Yousefi, Hassan, Abbasifard, Mitra. 2020. MTHFR gene polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis based on 16 studies. In Clinical rheumatology, 39, 2267-2279. doi:10.1007/s10067-020-05031-5. https://pubmed.ncbi.nlm.nih.gov/32170488/

5. Tabatabaei, Razieh Sadat, Fatahi-Meibodi, Neda, Meibodi, Bahare, Karimi-Zarchi, Mojgan, Neamatzadeh, Hossein. 2020. Association of Fetal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects: A Systematic Review and Update Meta-Analysis. In Fetal and pediatric pathology, 41, 225-241. doi:10.1080/15513815.2020.1775734. https://pubmed.ncbi.nlm.nih.gov/32536242/