Several studies have found genetic association between the MTHFR gene and autism in Caucasian and Indian population cohorts as well as AGRE cohorts. However, another study found no genetic association between the MTHFR gene and autism in a Brazilian population cohort. Separately, a study showed that the MTHFR C677T variant is associated with greater depressed mood during pregnancy.
Molecular Function
The encoded protein catalyzes the conversion of 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.
Case-control meta-analysis consisting of 13 studies (9 from Caucasian population, 4 from Asian population) comprising 1978 cases and 7257 controls. 8 of these studies were used in the C677T meta-analysis in PMID 23653228.
Mthfr het mutants born of het mothers show developmental delay, decreased weight, spatial memory and social memory. Mthfr mutants born of wildtype mothers show decreased nest building behavior, social memory and spatial working memory, and increased stereotypy indicating some behaviors are affected more by maternal genotype than by offspring genotype. Some phenotypes are rescues by a C1 enriched diet in the periconceptional and postnatal period.
References
Type
Title
Author, Year
Primary
Maternal and offspring methylenetetrahydrofolate-reductase genotypes interact in a mouse model to induce autism spectrum disorder-like behavior.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Exon 3 of the Mthfr gene was interrupted with the insertion of a neomycin resistance cassette. Controls include wildtype offsprings born to wild-type dams that were fed a control diet (Wt-Wt-CD, control group)
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: Balb/cAnNCrlBR
ES Cell Line: Mutant ES Cell Line: Model Source: Prof. Rima Rozen, McGill University, Montreal, QC, Canada (PMID 11181567)
Model Type:
Transgenerational
Model Genotype:
Wild-type
Mutation:
Wildtype offspring born to Mthfr het dams that were fed a control diet (Wt-Het-CD, control group2). Mothers carry a her mutation in exon 3 of the Mthfr gene which was interrupted with the insertion of a neomycin resistance cassette. Controls include wildtype offsprings born to wild-type dams that were fed a control diet (Wt-Wt-CD, control group). The model seeks to compare the effect of the maternal genotype versus the effect of the offspring genotype (in model M_MTHFR_1_KO_HT) on the phenotype to determine the transgenerational effects of the Mthfr loss-of-function KO mutantion.
Allele Type: NA
Strain of Origin: Genetic Background: Balb/cAnNCrlBR
ES Cell Line: Mutant ES Cell Line: Model Source: Prof. Rima Rozen, McGill University, Montreal, QC, Canada (PMID 11181567)
Description: Het mutant offsprings of het mothers show delayed development of the geotaxis reflex compared with wt offsprings of wt mothers.
Exp Paradigm: NA
Description: Male het offsprings of het mothers show a delay in their ability to stay on the rotarod compared with male wt offsprings of wt mothers.
Exp Paradigm: NA
Description: Mutants show decrease in psd95 levels, a post-synaptic protein in glutamatergic synapses, compared with controls.
Exp Paradigm: Cerebral cortex
Description: Male mutants show decrease in vgat but not in gad protein levels, representing gabaergic neurons, in the cerebral cortex compared with controls.
Exp Paradigm: Cerebral cortex
Description: Het male offsprings of het mothers show decrease in interaction with the mouse box over the empty box compared with wt male offsprings of wt mothers.
Exp Paradigm: NA
Description: Het mutant male and female offsprings of het mothers require more time to return to their nests when placed 5 cm from it compared with wt offsprings of wt mothers.
Exp Paradigm: Measures the ability of the pup to find its way back to its nest after being placed at a distance of 5 cm from it.
Description: Het male mice of het mothers show no change in time spent with the novel or familiar mouse whereas wt male mice of wt mothers spent more time with the novel mouse than with the familiar mouse.
Exp Paradigm: NA
Description: Het mutant offsprings of het mothers show decrease in body weight on p6, p7, p9, p10, p11, p12, and p14 compared with wt offsprings of wt females.
Exp Paradigm: NA
Description: Het mutant offsprings of het females show delay in eyelid opening at p7 and p14, ear canal opening at p7, 8, 10, 11, and 13, delay in teeth emergence at p5, and delay in fur appearance at p5 and p7 compared with wt offsprings of wt females.
Exp Paradigm: NA
Description: Het male offsprings of het mothers show increase in time spent in the center compared with het male offsprings of wt mothers.
Exp Paradigm: NA
Description: Het female offsprings of het mothers show decrease in time spent in the center compared with wt female offsprings of wt or het mothers.
Exp Paradigm: NA
Description: Male mutants show decrease in number of entries into the center of the field and duration spent in the center of the field compared with controls. female mutants show increase in the number of entries into the periphery of the field, and the distance travelled in the periphery compared with controls.
Exp Paradigm: NA
Description: Female het offsprings of het mothers show no change in time spent sniffing familiar versus non-familiar objects whereas female wt offsprings of wt and het mothers spend more time with the novel versus the familiar objects. male het offsprings of het mothers show no significant change in the time spent sniffing the novel versus the familiar objects whereas wt male offsprings of wt mothers spent more time with the novel than with the familiar objects.
Exp Paradigm: NA
Description: Female het offsprings of het mothers show decrease in time spent sniffing an inanimate object compared with wt females of wt mothers.
Exp Paradigm: NA
Description: Male mutants show no change in methionine levels in the cerebral cortex (p=0.06) and basal forebrain, and decrease in betaine and betaine to choline ratios in the cerebral cortex and basal forebrain compared with controls. female mutants show increase in methionine levels in the cerebral cortex and basal forebrain, and decrease in betaine levels in the basal forebrain and no change in betaine to choline ratios in the cerebral cortex compared with controls.
Exp Paradigm: Levels of choline, betaine, methionine, dimethylglycine, acetylcholine, phosphocholine, phosphatidylcholine, glycerophosphocholine, sphingomyelin, s-adenosylmethionine and s-adenosylhomocysteine were estimated in the liver, cerebral cortex, and basal forebrain.
Description: Wt offsprings of het females show delay in developing righting reflex at p6 compared with wt offsprings of wt mothers but no change at p4-p5, and p7-p9.
Exp Paradigm: NA
Description: Male wt offsprings of het mothers show a delay in their ability to stay on the rotarod compared with male wt offsprings of wt mothers.
Exp Paradigm: NA
Description: Male wt offsprings of het mothers show increase in parvalbumin positive interneurons in the l2 and l6 layers of the cerebral cortex compared with wt male offsprings of wt mothers.
Exp Paradigm: L2 and l6 layers of the cerebral cortex
Description: Models show no change in psd95 protein levels, a post-synaptic protein in glutamatergic synapses, compared with controls.
Exp Paradigm: Cerebral cortex
Description: Male and female models show decrease in vgat protein levels, representing gabaergic neurons, in the cerebral cortex compared with controls.
Exp Paradigm: Cerebral cortex
Description: Female wt offsprings of het mothers showed decrease in the number of marbles buried compared with female wt offsprings of wt mothers.
Exp Paradigm: NA
Description: Wt male mice of het mothers show increased in the time spent sniffing the stimulus mouse versus an empty box compared with wt male offsprings of wt mothers.
Exp Paradigm: NA
Description: Wt male and female offsprings of het mothers show no change in time to return to their nests when placed 5 cm from it compared with wt offsprings of wt mothers.
Exp Paradigm: Measures the ability of the pup to find its way back to its nest after being placed at a distance of 5 cm from it.
Description: Female mutants show decrease in latency to first interaction but no change in total time spent interacting with social stimulus compared with controls.
Exp Paradigm: NA
Description: Wt male mice of het mothers show no change in time spent with the novel or familiar mouse whereas wt male mice of wt mothers spent more time with the novel mouse than with the familiar mouse.
Exp Paradigm: NA
Description: Adult resident female wt offsprings of het mothers show increase in the duration of aggressive interactions (bs) compared with wt resident females of wt mothers. adult intruding female wt offsprings of het mothers show decrease in the number of times it crawls under the resident compared with intruding wt female offsprings of wt mothers.
Exp Paradigm: NA
Description: Wt offsprings of het females show delay in eyelid opening, ear canal opening, teeth emergence, and fur appearance compared with wt offsprings of wt females.
Exp Paradigm: NA
Description: Wt female offsprings of het mothers show increase in time spent in the center compared with wt female offsprings of wt mothers.
Exp Paradigm: NA
Description: Male models show decrease in the frequency of entries into the center of the field and spent less time in the center of the field compared with controls. female models enter the center of the field fewer times and spend more time in the periphery compared with controls.
Exp Paradigm: NA
Description: Wt male offsprings of het mothers show decrease in time spent in the center compared with wt male offsprings of wt mothers.
Exp Paradigm: NA
Description: Male models show no change in methionine levels in the cerebral cortex and basal forebrain, betaine and betaine to choline ratios in the cerebral cortex and forebrain compared with controls. female models show increase in methionine levels in the cerebral cortex but not in the basal forebrain, and no change in betaine in the basal forebrain or betaine to choline ratios in the levels in the cerebral cortex compared with controls.
Exp Paradigm: Levels of choline, betaine, methionine, dimethylglycine, acetylcholine, phosphocholine, phosphatidylcholine, glycerophosphocholine, sphingomyelin, s-adenosylmethionine and s-adenosylhomocysteine were estimated in the liver, cerebral cortex, and basal forebrain.
