Disease relevance of Mthfd1

• Methanol toxicity and formate oxidation in NEUT2 mice [1].
• Mice exposed to 32 ppm (nominal concentration) DCS for 2 or 4 weeks also exhibited depression of body weight gain, wheezing and piloerection [2].
• Spinal cord white matter is the major site of tissue damage resulting from decompression sickness (DCS or "the bends") [3].
• Why DCS occurs predominantly in the spinal cord and not in the brain is not known; neither is the exact pathological mechanism by which the spinal cord is damaged, nor how multiple sclerosis (MS)-like symptoms may ensue [3].

High impact information on Mthfd1

• The Mthfd1 gene encoding the cytoplasmic methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase enzyme (DCS) was inactivated in embryonic stem cells [4].
• Disruption of histidine catabolism in NEUT2 mice [5].
• Based on the excretion of urocanic acid it is estimated that NEUT2 mice catabolize approximately 40 micromol/day via the deamination pathway [5].
• The loss of urocanase activity in homozygous NEUT2 mice may allow these mice to survive the disruption in folate metabolism by sparing the liver cytosolic tetrahydrofolate pool [5].
• Histidase and formiminotransferase-cyclodeaminase, also on the histidine deamination pathway, had similar specific activities in normal and NEUT2 mice [5].

Chemical compound and disease context of Mthfd1

• Using male ICR mice, the LC50 and acute and subacute inhalation toxicity of dichlorosilane (SiH2Cl2, DCS) and the fate of DCS released into the air were investigated [2].

Biological context of Mthfd1

• Exposure to DCS was irritant or corrosive to the respiratory tract with both acute and subacute inhalation [2].

Associations of Mthfd1 with chemical compounds

• Unlike the heritable protein changes observed previously in the F1 offspring of sires exposed to N-ethyl-N-nitrosourea in which a protein variant was produced, both the NEUT1 and NEUT2 mutation events appear to prevent the production of any protein product [6].
• High doses of [(14)C]sodium formate (ip 100 mg/kg) were oxidized to (14)CO(2) at identical rates in normal and NEUT2 homozygous mice [1].
• Normal (CB6-F1) and NEUT2 heterozygous and homozygous mice had essentially identical LD(50) values for methanol, 6.08, 6.00, and 6.03 g/kg, respectively [1].
• In conclusion, DCS potentiates the anticonvulsant action of some classical antiepileptic drugs, most notably diazepam, phenobarbital, phenytoin and valproate [7].
• The degree of potentiation induced by DCS was greatest for diazepam, phenobarbital, phenytoin and valproate, less for carbamazepine and least for lamotrigine and felbamate [7].

Analytical, diagnostic and therapeutic context of Mthfd1

• Northern blot analysis suggests that a recently identified mitochondrial DCS (Prasannan, P., Pike, S., Peng, K., Shane, B., and Appling, D. R. (2003) J. Biol. Chem. 278, 43178-43187) is responsible for the synthetase activity [4].

References