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Relevance to Autism

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.
ASD
Positive Association
Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population.
ASD
Positive Association
Population- and family-based studies associate the MTHFR gene with idiopathic autism in simplex families.
ASD
Positive Association
The MTHFR 677C-->T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations.
ASD
Positive Association
Aberrations in folate metabolic pathway and altered susceptibility to autism.
ASD
Positive association
Association of MTHFR 677C>T and 1298A>C polymorphisms with susceptibility to autism: A systematic review and meta-analysis.
ASD
Positive Association
Study of C677T variant of methylene tetrahydrofolate reductase gene in autistic spectrum disorder Egyptian children.
ASD
Positive Association
Association between MTHFR gene polymorphisms and the risk of autism spectrum disorders: a meta-analysis.
ASD
Negative Association
MTHFR C677T is not a risk factor for autism spectrum disorders in South Brazil.
ASD
Support
Reanalysis of Trio Whole-Genome Sequencing Data Doubles the Yield in Autism Spectrum Disorder: De Novo Variants Present in Half
ASD
ADHD, ID, epilepsy/seizures
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
Homocystinuria due to MTHFR deficiency
ID, microcephaly
Support
Homocystinuria due to MTHFR deficiency, ASD, ADHD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression
ASD
Developmental regression
Highly Cited
A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.
Highly Cited
MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis.
Recent Recommendation
Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility.
ASD
Recent Recommendation
Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks fro...
Recent Recommendation
Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice.
Recent Recommendation
Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN163R001a 
 missense_variant 
 c.199C>T 
 p.Pro67Ser 
 Familial 
 Both parents 
 Multiplex 
 GEN163R002 
 missense_variant 
 c.1090C>T 
 p.Leu364Phe 
 De novo 
  
 Simplex 
 GEN163R003 
 missense_variant 
 c.136C>T 
 p.Arg46Trp 
 Unknown 
  
 Unknown 
 GEN163R004 
 missense_variant 
 c.776T>C 
 p.Val259Ala 
 Unknown 
  
  
 GEN163R005 
 missense_variant 
 c.130A>T 
 p.Asn44Tyr 
 De novo 
  
  
 GEN163R006a 
 missense_variant 
 c.199C>T 
 p.Pro67Ser 
 Familial 
 Both parents 
 Multiplex 
 GEN163R007 
 missense_variant 
 c.1409A>T 
 p.Glu470Val 
 Familial 
 Paternal 
 Simplex 
 GEN163R008 
 missense_variant 
 c.101C>T 
 p.Thr34Ile 
 Familial 
 Maternal 
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
1
Deletion-Duplication
 15
 
1
Deletion
 1
 
1
Deletion
 2
 
1
Duplication
 5
 
1
Deletion
 1
 
1
Deletion
 1
 
1
Duplication
 1
 
1
Duplication
 1
 
1
Deletion
 2
 
1
Deletion-Duplication
 15
 
1
Deletion
 2
 
1
Deletion
 2
 
1
Deletion
 3
 
1
Duplication
 1
 

Model Summary

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.
Additional
Prenatal Nutritional Intervention Reduces Autistic-Like Behavior Rates Among Mthfr-Deficient Mice.
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)
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Motor coordination and balance1
Decreased
 Accelerating rotarod test
 P4-p17
Negative geotaxis1
Decreased
 General observations
 P4-p17
Post-synaptic density size: excitatory synapses2
Decreased
 Western blot
 3 months
Neuronal number: inhibitory neurons2
Decreased
 Western blot
 3 months
Vision1
Decreased
 Cliff avoidance test
 P4-p17
Social approach1
Decreased
 Three-chamber social approach test
 11 weeks
Social scent marking or recognition1
Decreased
 Homing test
 P4-p17
Nest building behavior1
Decreased
 Nest building assay
 4 weeks
Social memory1
Decreased
 Three-chamber social approach test
 11 weeks
Nest building behavior2
Decreased
 Nest building assay
 3 months
Social memory2
Decreased
 Three-chamber social approach test
 NA
Size/growth1
Decreased
 Body weight measurement
 P4-p15
Developmental trajectory1
Decreased
 General observations
 P4-p17
Anxiety1
Increased
 Open field test
 11 weeks
Anxiety2
Increased
 Open field test
 3 months
Anxiety1
Decreased
 Open field test
 11 weeks
Cognitive flexibility1
Decreased
 Novel object interaction test
 11 weeks
Object recognition memory1
Decreased
 Novel object recognition test
 11 weeks
Metabolite levels: neurometabolites2
Abnormal
 Liquid chromatography-mass spectrometry (lc-ms)
 3 months
Chromatin modification: histone modification: open chromatin2
Increased
 Western blot
 3 months
Cognitive flexibility1
 No change
 Novel object interaction test
 11 weeks
Chromatin modification: histone modification: open chromatin2
 No change
 Western blot
 3 months
General locomotor activity2
 No change
 Open field test
 3 months
General locomotor activity: ambulatory activity1
 No change
 Open field test
 11 weeks
General locomotor activity: ambulatory activity2
 No change
 Open field test
 3 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 P4-p17
Righting response1
 No change
 Righting reflex test
 P4-p17
Neuronal number: inhibitory neurons2
 No change
 Western blot
 3 months
Neuronal number: interneurons1
 No change
 Immunofluorescence staining
 3 months
Neuroreceptor levels: glutamate receptors: ampa receptors2
 No change
 Western blot
 3 months
Neuroreceptor levels: glutamate receptors: nmda receptors2
 No change
 Western blot
 3 months
Neurotransporter expression2
 No change
 Western blot
 3 months
Post-synaptic density size: inhibitory synapses2
 No change
 Western blot
 3 months
Repetitive digging1
 No change
 Marble-burying test
 11 weeks
Repetitive digging2
 No change
 Marble-burying test
 3 months
Repetitive digging1
 No change
 Marble-burying test
 4 weeks
Stereotypy: chewing behavior1
 No change
 Observation of repetitive behavior
 11 weeks
Aggression1
 No change
 Resident-intruder test
 4 weeks; 11 weeks
Nest building behavior1
 No change
 Nest building assay
 11 weeks
Nest building behavior2
 No change
 Nest building assay
 3 months
Rearing behavior2
 No change
 Open field test
 3 months
Social approach1
 No change
 Three-chamber social approach test
 11 weeks
Social approach2
 No change
 Three-chamber social approach test
 3 months
Social memory1
 No change
 Three-chamber social approach test
 11 weeks
Social memory2
 No change
 Three-chamber social approach test
 3 months
 Not Reported:

 

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