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Relevance to Autism

De novo missense variants in the NEUROD2 gene that were experimentally shown to disrupt protein function in Xenopus were identified in three individuals presenting with developmental delay with or without seizures (Sega et al., 2019; Mis et al., 2021); follow-up of these three individuals in Runge et al., 2021 revealed that two of these patients also presented with autism spectrum disorder. In addition to follow-up of these three previously published patients, Runge et al., 2021 characterized three novel patients with experimentally-confirmed loss-of-function missense variants in NEUROD2 and two patients with large de novo deletions encompassing NEUROD2; all five of these novel patients presented with autism spectrum disorder, intellectual disability, and speech disturbance. Runge et al., 2021 also demonstrated that Neurod2 knockout mice displayed altered laminar organization and cortical gene expression, radial over-migration of cortical projection neurons, altered excitatory synapse density and turnover, social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures; mice that were heterozygous for Neurod2 had similar deficits, and specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypies observed in constitutive knockout mice.

Molecular Function

This gene encodes a member of the neuroD family of neurogenic basic helix-loop-helix (bHLH) proteins. Expression of this gene can induce transcription from neuron-specific promoters, such as the GAP-43 promoter, which contain a specific DNA sequence known as an E-box. The product of the human gene can induce neurogenic differentiation in non-neuronal cells in Xenopus embryos, and is thought to play a role in the determination and maintenance of neuronal cell fates.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy
DD, epilepsy/seizures
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Expansion of NEUROD2 phenotypes to include developmental delay without seizures
ASD, DD
ADHD
Recent Recommendation
Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons
ASD, DD, ID
Epilepsy/seizures
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1256R001 
 missense_variant 
 c.388G>C 
 p.Glu130Gln 
 De novo 
  
 Simplex 
 GEN1256R002 
 missense_variant 
 c.401T>C 
 p.Met134Thr 
 De novo 
  
 Simplex 
 GEN1256R003 
 missense_variant 
 c.488T>C 
 p.Leu163Pro 
 De novo 
  
 Simplex 
 GEN1256R004 
 missense_variant 
 c.703G>A 
 p.Ala235Thr 
 Unknown 
  
 Unknown 
 GEN1256R005 
 missense_variant 
 c.385C>T 
 p.Arg129Trp 
 De novo 
  
 Simplex 
 GEN1256R006 
 missense_variant 
 c.388G>C 
 p.Glu130Gln 
 De novo 
  
 Simplex 
 GEN1256R007 
 missense_variant 
 c.804C>A 
 p.His268Gln 
 Familial 
 Paternal 
 Multiplex 
 GEN1256R008 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN1256R009 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN1256R010 
 stop_lost 
 c.1148G>C 
 p.Ter383SerextTer106 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
17
Deletion-Duplication
 78
 
17
Duplication
 1
 
17
Duplication
 1
 

Model Summary

Neurod2 KO embryos show increased migration of cortical projection neurons and abnormal cortical thickness and lamination. Neurod2 KO juvenile and adult mice show misregulated spine density and turnover in apical but not basal

References

Type
Title
Author, Year
Primary
Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons
Model Type: Genetic LOF
Model Genotype: Homozygous
Mutation: The entire coding region of the gene was replaced with an in-frame lacZ gene followed by a loxP flanked neomycin selection cassette. For layer cortical morpho-functional analyses,Neurod2 KO mice were bred with mice expressing eGFP under the Thy-1 promoter. AAV-TurboRFP was injected to assess neuronal expression in L2/3 of M1 in Neurod2 WT and KO mice, and measure spine density.
Allele Type: knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6N*129Sv
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Bormuth I, et al, J Neurosci. 2013;33:641â??51 (23303943); Pieper A, Sci Rep 2019 Feb 5;9(1):1448 (30723302)
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Rearing behavior1
Increased
 Open field test
 8â??14-weeks
General locomotor activity1
Increased
 Open field test
 8â??14-weeks
Morphology and size of the corpus callosum1
Decreased
 Immunohistochemistry
 1 month
Cortical lamination1
Abnormal
 Immunohistochemistry
 1 month, P7
Neuronal morphology1
Abnormal
 Immunohistochemistry
 1 month
Dendritic architecture: spine turnover1
Increased
 Immunohistochemistry
 1 month
Neuronal migration1
Increased
 Immunofluorescence staining
 E13.5-E18.5, P7
Dendritic architecture: spine density1
Abnormal
 Immunohistochemistry
 1, 4 months
Neocortex morphology1
Abnormal
 Immunohistochemistry
 1 month
Cortical thickness1
Decreased
 Immunohistochemistry
 1 month, P7
Neuronal ion channel activity1
Abnormal
 Quantitative PCR (qRT-PCR)
 1 month
Miniature post synaptic current amplitude: inhibitory1
Increased
 Whole-cell patch clamp
 1 month
Hyperpolarization activated cation currents1
Increased
 Whole-cell patch clamp
 1 month
EPSP-spike relationship1
Increased
 Whole-cell patch clamp
 1 month
Seizures1
Increased
 Observation of seizures
 8â??14-weeks
Social memory1
Decreased
 Three-chamber social approach test
 8â??14-weeks
Social approach1
Decreased
 Three-chamber social approach test
 8â??14-weeks
Mortality/lethality1
Increased
 Observation of seizures
 8â??14-weeks
Differential gene expression1
Abnormal
 RNA sequencing
 1 month
Differential gene expression1
Abnormal
 RNA sequencing
 P28
Differential gene expression1
Abnormal
 Quantitative PCR (qRT-PCR)
 1 month
Object recognition memory1
 No change
 Novel object recognition test
 8â??14-weeks
Anatomical projections and connectivity1
 No change
 Retrograde labeling assay
 1 month
Cell proliferation: neural precursors1
 No change
 Immunohistochemistry
 E18, P7, P30
Dendritic architecture: dendritic tree complexity1
 No change
 Immunohistochemistry
 1 month
Synapse density: Inhibitory1
 No change
 Immunohistochemistry
 1 month
Action potential property: after hyperpolarization1
 No change
 Whole-cell patch clamp
 1 month
Action potential property: amplitude1
 No change
 Whole-cell patch clamp
 1 month
Action potential property: threshold1
 No change
 Whole-cell patch clamp
 1 month
Intrinsic membrane properties1
 No change
 Whole-cell patch clamp
 1 month
Membrane potential1
 No change
 Whole-cell patch clamp
 1 month
Miniature post synaptic current amplitude: excitatory1
 No change
 Whole-cell patch clamp
 1 month
Miniature post synaptic current frequency: excitatory1
 No change
 Whole-cell patch clamp
 1 month
Miniature post synaptic current frequency: inhibitory1
 No change
 Whole-cell patch clamp
 1 month
Neuronal apoptosis1
 No change
 Immunohistochemistry
 E18, P7, P30
Synaptic transmission1
 No change
 Whole-cell patch clamp
 1 month
Circling1
 No change
 Open field test
 8â??14-weeks
 Not Reported:

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