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Relevance to Autism

Several studies have found genetic association between the EN2 gene and autism. In particular, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Molecular Function

The encoded protein is a transcription factor.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder.
ASD
Positive Association
Heterogeneous association between engrailed-2 and autism in the CPEA network.
ASD
Positive Association
Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus.
ASD
Positive Association
Association of the homeobox transcription factor gene ENGRAILED 2 with autistic disorder in Chinese children.
ASD
Positive Association
Association of the ENGRAILED 2 (EN2) gene with autism in Chinese Han population.
ASD
Negative Association
The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families.
ASD
Negative Association
Association study of the CNS patterning genes and autism in Han Chinese in Taiwan.
ASD
Negative Association
No association between the EN2 gene and autistic disorder.
ASD
Support
Autism associated gene, engrailed2, and flanking gene levels are altered in post-mortem cerebellum.
Support
Cut-like homeobox 1 and nuclear factor I/B mediate ENGRAILED2 autism spectrum disorder-associated haplotype function.
Support
ASD
Support
Whole-genome deep-learning analysis identifies contribution of noncoding mutations to autism risk
ASD
Support
Whole-exome sequencing identifies a novel heterozygous missense variant of the EN2 gene in two unrelated patients with autism spectrum disorder.
ASD
Support
Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder.
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Unknown diagnosis
Highly Cited
Expression patterns of the homeo box-containing genes En-1 and En-2 and the proto-oncogene int-1 diverge during mouse development.
Highly Cited
Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants.
Recent Recommendation
Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal...
Recent Recommendation
Engrailed-2 regulates genes related to vesicle formation and transport in cerebellar Purkinje cells.
Recent Recommendation
Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein.
Recent Recommendation
Tissue-specific enhancer functional networks for associating distal regulatory regions to disease
ASD
Recent Recommendation
En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder.
Recent Recommendation
Impaired Neuronal Differentiation of Neural Stem Cells Lacking the Engrailed-2 Gene.
Recent Recommendation
The transcription factor Engrailed-2 guides retinal axons.
Recent Recommendation
Increased signaling by the autism-related Engrailed-2 protein enhances dendritic branching and spine density, alters synaptic structural matching, ...
Recent Recommendation
Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in aut...

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN078R001 
 synonymous_variant 
 c.996C>T 
 p.Ser332= 
 De novo 
  
 Unknown 
 GEN078R002 
 missense_variant 
 c.425C>G 
 p.Pro142Arg 
 Familial 
 Maternal 
 Multiplex 
 GEN078R003 
 missense_variant 
 c.425C>G 
 p.Pro142Arg 
 Familial 
 Paternal 
 Simplex 
 GEN078R004 
 intergenic_variant 
 C>T 
  
 De novo 
  
 Simplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN078C001 
 intron_variant 
 rs1861972 
 c.686-1073G>A 
 A to G 
 AGRE 
 Discovery 
 GEN078C002 
 intron_variant 
 rs1861973 
 c.686-921T>C 
 C to T 
 AGRE 
 Discovery 
 GEN078C003 
 intron_variant 
 rs1861972 
 c.686-1073G>A 
 A/G 
 AGRE, NIMH 
 Replication 
 GEN078C004 
 intron_variant 
 rs1861973 
 c.686-921T>C 
 C/T 
 AGRE, NIMH 
 Replication 
 GEN078C005 
 intron_variant 
 rs1861972 
 c.686-1073G>A 
 A/G 
 CPEA 
 Replication 
 GEN078C006 
 intron_variant 
 rs3824068 
 c.686-1568C>T 
 A/G 
 Chinese Han 
 Discovery 
 GEN078C007 
 intron_variant 
 rs1861972 
 c.686-1073G>A 
 A/G 
 Chinese Han 
 Replication 
 GEN078C008 
 intron_variant 
 rs1861973 
 c.686-921T>C 
 C/T 
 Chinese Han 
 Replication 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
7
Deletion
 2
 
7
Duplication
 1
 
7
Duplication
 1
 
7
Duplication
 1
 
7
Deletion
 4
 
7
Deletion-Duplication
 5
 
7
Deletion
 2
 
7
Deletion
 7
 
7
Deletion
 3
 
7
Deletion-Duplication
 30
 

Model Summary

Homozygous knockout mice display foliation defects in adult cerebellum.

References

Type
Title
Author, Year
Additional
Two Pax2/5/8-binding sites in Engrailed2 are required for proper initiation of endogenous mid-hindbrain expression.
Primary
Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox.
Additional
En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder.
Additional
Increased susceptibility to kainic acid-induced seizures in Engrailed-2 knockout mice.
Additional
Loss of GABAergic neurons in the hippocampus and cerebral cortex of Engrailed-2 null mutant mice: implications for autism spectrum disorders.
Additional
Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants.

M_EN2_4_PBDNEO_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Targeted deletion of the two Pax2/5/8-binding sites in En2 locus by homologous recombination with neo casette (PBDNEO).
Allele Type: Targeted (Deletion)
Strain of Origin: 129/SvEv
Genetic Background: Not Specified
ES Cell Line: R1; W4
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_EN2_5_PBD_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Cre/loxP mediated deletion of En2 Pax2/5/8-binding sites (PBD).
Allele Type: Targeted (Deletion)
Strain of Origin: 129/SvEv
Genetic Background: Not Specified
ES Cell Line: R1; W4
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_EN2_1_HD_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Targeted deletion of homeobox domain (HD) of En2 gene.
Allele Type: Targeted (Deletion)
Strain of Origin: C57BL/6; BALB/c
Genetic Background: C57BL/6; CD1; 129/Sv
ES Cell Line: D3
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_EN2_2_HD_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Targeted deletion of homeobox domain (HD) of En2 gene.
Allele Type: Targeted (Deletion)
Strain of Origin: C57BL/6; BALB/c
Genetic Background: C57BL/6; CD1; 129/Sv
ES Cell Line: D3
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_EN2_3_NTD_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Targeted deletion of exon 1 including N-terminal (NTD) of En2 gene.
Allele Type: Targeted (Deletion)
Strain of Origin: C3H
Genetic Background: CD1; 129/Sv
ES Cell Line: D3
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_EN2_4_PBDNEO_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Gene expression1
Decreased
Description: Decreased en2 rna expression
Exp Paradigm: En2 rna expression
 In situ hybridization (ish)
 E8.5-e17.5
Brain morphology1
 No change
 NA
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_EN2_5_PBD_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Gene expression1
Decreased
Description: Decreased en2 rna expression in anterior region with normal expression as development progressed
Exp Paradigm: En2 rna expression
 In situ hybridization (ish)
 E7.5-e17.5
General characteristics1
 No change
 General observations
 Unreported
Brain morphology1
 No change
 NA
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_EN2_1_HD_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Motor coordination and balance2
Abnormal
Description: Abnormal muscle coordination
Exp Paradigm: Rota-rod test
 Accelerating rotarod test
 P21-p27
Cerebellar morphology5
Decreased
Description: Abnormal location of boundary between anterior and posterior cerebellum at the base of intercrural fissure between vi and vii lobes and abnormal staining pattern in 4 regions of cerebellum: crus i, crus ii, paramedial lobe, paraflocculus, and lobe viii & ix
Exp Paradigm: Detection of lacz expression under en-2 enhancer and promoter restricted to granular and molecular layers
 Histology
 Unreported
Brain morphology5
Decreased
Description: Decreased cerebellar anlage size; decreased extent of fusion of cerebellar rudiments; decreased size of cerebellum and colliculi
Exp Paradigm: Dissection and histological analysis
 Histology
 E13.5-e16.5
Neuronal number: interneurons4
Decreased
Description: Decreased number of pv and som interneurons in layers ii-iii of somatosensory cortex
Exp Paradigm: Pv, sst
 In situ hybridization (ish)
 3-5 months
Cerebellar foliation5
Decreased
Description: Delayed fissure formation; absence of ansoparamedial fissure
Exp Paradigm: Comparison of saggital sections of cerebellum
 Histology
 P0- p7
Neuronal number: interneurons4
Decreased
Description: Decreased number of neuropeptide y, somatostatin, parvalbumin-positive interneurons in the hilus
Exp Paradigm: Npy, sst, pv
 Immunohistochemistry
 3-5 months
Cerebellar foliation5
Decreased
Description: Abnormal fissure formation; developmental delay; abnormal development of posterior fissure 2/py; abnormal ixth lobe shape and size; no change in anterior region of cerebellum
Exp Paradigm: Analysis of mid-line sagittal cresyl-violet stained sections
 Histology
 P0-p9
Hippocampal morphology3
Abnormal
Description: Abnormal pyramidal cell layer and mossy fiber pathway; cell loss and tissue sclerosis; increased npy immnoreactivity in mossy fibers of dentate gyrus
Exp Paradigm: Immunostainig for pan-neuronal marker neun; npy immunohistochemistry
 Immunohistochemistry
 Unreported
Brain morphology1
Decreased
Description: Decreased cerebellar size, both rostro-caudally and in the mediolateral expansion; abnormal foliation with abnormal fissure pattern, altered branching pattern, and decreased extent of the lobules
Exp Paradigm: Microscopic examination of brain
 Histology
 8 weeks
Neurotransmitter release: serotonin2
Increased
Description: Increased levels of serotonin, 5-hydroxyindolacetic acid in cerebellum; no change in level in hippocampus, striatum, and frontal cortex
Exp Paradigm: Hplc-electrochemical detection
 High-performance liquid chromatography (hplc)
 3 months
Self grooming: perseveration2
Increased
Description: Increased self grooming behavior
Exp Paradigm: General observations
 General observations
 3-4 months
Seizure threshold3
Increased
Description: Increased susceptibility to kainic acid induced seizures with progression to severe tonic-clonic seizures
Exp Paradigm: Response to 20 mg/kg dose of kainic acid injection
 Observation of chemically induced seizures
 Unreported
Aggression2
Decreased
Description: Decreased aggressive behavior; decrease in number of attacks to an intruder mouse
Exp Paradigm: Resident intruder test
 Resident-intruder test
 4-5 months
Juvenile play2
Decreased
Description: Decreased juvenile play, like chasing, pushing under, crawling over the partner, social sniffing, and allogrooming
Exp Paradigm: General observations
 General observations
 4-6 weeks
Exploratory activity2
Decreased
Description: Decreased exploratory behavior
Exp Paradigm: Modified open-field with objects
 Open field test
 3-4 months
Spatial learning2
Decreased
Description: Decreased spatial learning; deficit in performance of hidden platform taks; longer escape latency
Exp Paradigm: Hidden platform test for spatial memory and navigation.
 Morris water maze test
 Unreported
Marker expression3
Decreased
Description: Reduced expression of gabaergic markers, parvalbumin and somatostatin in ca3 pyramidal layer and stratum lcunosum moleculare
Exp Paradigm: Gabaergic marker expression
 Immunohistochemistry
 Unreported
Gene expression3
Decreased
Description: Decreased levels in hippocampus and cerebral cortex; increased levels in ventral midbrain and cerebellum
Exp Paradigm: En2 mrna expression
 Quantitative pcr (qrt-pcr)
 Unreported
Marker expression4
Decreased
Description: Decreased mrna expression in somatosensory cortex of pv, npy, and som
Exp Paradigm: Gabaergic marker expression
 Quantitative pcr (qrt-pcr)
 3-5 months
Marker expression4
Decreased
Description: Decreased expression of npy, pv, and som mrna
Exp Paradigm: Gabaergic marker expression
 Quantitative pcr (qrt-pcr)
 3-5 months
Protein expression level evidence1
Decreased
Description: Decreased en2 protein expression
Exp Paradigm: En2 protein expression
 Western blot
 P9.5
Gene expression3
Increased
Description: Increased c-fos and c-jun, immediate early genes, mrna in layers 2-3 and 5-6
Exp Paradigm: Immediate early gene (ieg) induction
 In situ hybridization (ish)
 Unreported
General characteristics3
 No change
 General observations
 Unreported
General characteristics1
 No change
 General observations
 Unreported
Marker expression4
 No change
 Quantitative pcr (qrt-pcr)
 3-5 months
Marker expression4
 No change
 Quantitative pcr (qrt-pcr)
 3-5 months
Protein expression level evidence1
 No change
 Western blot
 P8.5, p9.5
General locomotor activity2
 No change
 Open field test
 3-4 weeks
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Unreported
Negative geotaxis2
 No change
 Negative geotaxis test
 3-4 weeks
Righting response1
 No change
 Righting reflex test
 Unreported
Righting response2
 No change
 Righting reflex test
 3-4 weeks
Swimming ability1
 No change
 Swim test
 Unreported
Brain anatomy1
 No change
 Microscopic analysis
 P8, p9, p12
Brain morphology5
 No change
 Histology
 E17.5
Brain morphology1
 No change
 Histology
 2 months
Hippocampal morphology4
 No change
 Photomicrographic analysis
 3-5 months
Neuronal number: interneurons4
 No change
 Immunohistochemistry
 3-5 months
Neuronal number: interneurons4
 No change
 In situ hybridization (ish)
 3-5 months
Neuronal number: interneurons4
 No change
 In situ hybridization (ish)
 3-5 months
Somatosensory cortical map architecture4
 No change
 Immunohistochemistry
 3-5 months
Vision2
 No change
 Morris water maze test
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_EN2_2_HD_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Motor coordination and balance1
 No change
 Accelerating rotarod test
 Unreported
Righting response1
 No change
 Righting reflex test
 Unreported
Swimming ability1
 No change
 Swim test
 Unreported
Brain morphology1
 No change
 Histology
 2 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_EN2_3_NTD_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Protein expression level evidence1
Decreased
Description: Absence of en2 protein expressed in cerebellum
Exp Paradigm: En2 protein expression
 Immunohistochemistry
 Unreported
General characteristics1
 No change
 General observations
 Unreported
Brain morphology1
 No change
 Histology
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior





Download EN2's Cytoscape file


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