The enzyme methylenetetrahydrofolate reductase (MTHFR) is a part of the homocysteine and folate metabolic pathways, affecting the methylations of DNA, RNA, and proteins. Mthfr deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between the epigenetic influence of Mthfr deficiency and neonatal exposure to the GABA potentiating drug vigabatrin (GVG) in mice has been shown to have gender-dependent effects on mice anxiety and to have memory impairment effects in a gender-independent manner. Here we show that Mthfr deficiency interacts with neonatal GABA potentiation to alter social behavior in female, but not male, mice. This impairment was associated with a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the female cortex. Reelin and fragile X mental retardation 1 protein (FMRP) levels and membrane GluR1/GluR2 ratios were elevated in wild-type mice treated neonatally with GVG and in Mthfr+/- mice treated with saline, but not in Mthfr+/- mice treated with GVG, compared with control groups (wild type treated with saline). A minor influence on the levels of these proteins was observed in male mice cortices, possibly due to high basal protein levels. Interaction between gender, genotype, and treatment was also observed in the GABA pathway. In female mice, GABA Aα2/gephyrin ratios were suppressed in all test groups; in male mice, a genotype-specific enhancement of GABA Aα2/gephyrin was observed. The lack of an effect on either reln or Fmr1 transcription suggests post-transcriptional regulation of these genes. Taken together, these findings suggest that Mthfr deficiency may interact with neonatal GABA potentiation in a gender-dependent manner to interrupt synaptic function. This may illustrate a possible mechanism for the epigenetic involvement of Mthfr deficiency in neurodevelopmental disorders.
5,10-Methylenetetrahydrofolate reductase (MTHFR) is crucial for converting a specific compound in the folate cycle, impacting homocysteine levels in the body.
A patient with epilepsy showed elevated homocysteine and carried two genetic variants in the MTHFR gene, which were analyzed for their effects on gene splicing.
The study reveals complex splicing patterns and emphasizes the importance of monitoring homocysteine levels, even in family members without noticeable symptoms, as they may still carry risks associated with MTHFR deficiency.
Aim: Remethylation disorders such as 5,10-methylenetetrahydrofolate reductase () deficiency reduce the remethylation of homocysteine to methionine. The resulting hyperhomocysteinemia can lead to serious neurological consequences and multisystem toxicity. The role of genotypes has not been investigated in patients with Rett Syndrome (RTT).
Department of Clinical Laboratory, Zhuhai 5th People's Hospital, Zhuhai, Guangdong 519055, China; Department of Clinical Laboratory, Zhuhai Center for Maternal and Child Health Care, Zhuhai, Guangdong 519001, China. Electronic address:
The methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) are crucial enzymes in the folic acid cycle that help regulate levels of methionine and homocysteine in the body.
Polymorphisms (genetic variations) in the MTHFR gene can impair enzyme function, leading to elevated homocysteine levels, which is linked to increased risks of vascular complications and potentially contributes to diabetes-related health issues.
This review highlights the emerging role of MTHFR gene polymorphism as a risk factor for diabetes, emphasizing its impact on inflammation and insulin resistance
