Academic journal article Iranian Journal of Public Health

Leber Hereditary Optic Neuropathy: Do Folate Pathway Gene Alterations Influence the Expression of Mitochondrial DNA Mutation?

Academic journal article Iranian Journal of Public Health

Leber Hereditary Optic Neuropathy: Do Folate Pathway Gene Alterations Influence the Expression of Mitochondrial DNA Mutation?

Article excerpt


Background: Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy leading to the loss of central vision. The primary cause of vision loss is mutation in the mitochondrial DNA (mtDNA), however, unknown secondary genetic and/or epigenetic risk factors are suggested to influence its neuropathology. In this study folate gene polymorphisms were examined as a possible LHON secondary genetic risk factor in Iranian patients.

Methods: Common polymorphisms in the MTHFR (C677T and A1298C) and MTRR (A66G) genes were tested in 21 LHON patients and 150 normal controls.

Results: Strong associations were observed between the LHON syndrome and C677T (P= 0.00) and A66G (P= 0.00) polymorphisms. However, no significant association was found between A1298C (P =0.69) and the LHON syndrome.

Conclusion: This is the first study that shows MTHFR C677T and MTRR A66G polymorphisms play a role in the etiology of the LHON syndrome. This finding may help in the better understanding of mechanisms involved in neural degeneration and vision loss by LHON and hence the better treatment of patients.

Keywords: LHON, MTHFR, MTRR, Folate, Folic acid.


Mitochondrial DNA mutations at nucleotide (nt) position 3460, 11778, 14459 and 14484 has been shown to be primary LHON mutations with similar or different phenotypes (1-5). These primary mitochondrial DNA mutations cause energy deficits and have been postulated to lead to neuronal injury via an exocytotoxic mechanism. However, their derangement may be relatively subtle and not sufficient to cause visual loss in LHON (6, 7). Furthermore, the cause for severity of the optic neuropathy and incomplete penetrance of vision loss has been inadequately explained and unknown secondary genetic or environmental factors have been indicated to have a role (8-10).

There is a relationship between the mitochondrion and folate derivatives of cell folate metabolism. The folate pathway in the mitochondrion contributes to the entire cellular metabolism of mammals and the mitochondrion has been suggested as a target organelle for the cytotoxic effect of antifolates (11). The active form of folate, tetrahydrofolate (THF), functions to transfer single carbon units that exist in different oxidation states, which is then converted by enzymes located in cytosolic and mitochondrial compartments (12, 13). Two enzymes critical in the folate metabolic pathway are products of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes which are involved in the synthesis of 5-methyltetrahydrofolate and methionine, respectively. 5-Methyltetrahydrofolate (MTHF), the predominate circulating form of folate, acts as the methyl donor for remethylation of homocysteine to methionine by the vitamin B12 dependent enzyme methionine synthase (14, 15).

In the case of the MTHFR gene, transition of cytosine (C) to thymidine (T) at nt-677 causes an alanine to valine substitution, leading to an increase in MTHFR thermolability and reduction of enzyme activity. In the heterozygous C/T and the homozygous T/T genotypes, activities decrease to approximately 35% and 70%, respectively, as compared to that observed for the normal C/C genotype (16, 17). A second common mutation in MTHFR A1298C involves a transversion mutation leading to a glutamate to alanine substitution. A moderate decrease in enzyme activity is observed more frequently in the homozygous mutant (CC) genotype, but with no change in enzyme thermolability (16). Severe MTHFR deficiency is characterized by neurological abnormalities, problems in nerve myelination, vascular disease, neural tube defects and neurodegenerative diseases such as Alzheimer and Parkinson's (14, 16-19). Methionine synthase reductase (MTRR) keeps methionine synthesis enzyme in an active state for remethylation of homocysteine to methionine. Polymorphism at position A66G leads to replacement of methionine with isoleucine, thus reducing enzyme activity and increasing homocyteine levels (17, 20). …

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