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
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)
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
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.
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)
Model Type:
Genetic LOF
Model Genotype:
Homozygous
Mutation:
Neurod2 Tm1a mice, with a conditional allele based on theâ??knockout-firstâ?? design were generated on a C57BL/6N background using cell clone EPD0422_5_B06 from the Knock Out Mouse Project at UC Davis (http://www.komp.org), in which the only coding exon (exon 2) was flanked by loxP sites. Neurod2^flox/flox mice, or Tm1c mice for Neurod2, were produced by crossing Tm1a mice with actin-Flippase mice (Jackson Stock N° 003800). For forebrain-deletion experiments, Neurod2flox/flox mice were crossed with Emx1IRESCre mice.
Allele Type: conditional knockout
Strain of Origin: C57BL/6N
Genetic Background: Not reported
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Gorski et al, J Neurosci, 2002 (12151506)
Description: Decreased cortical areas m1 and s1, normal aspect and thickness of the cortical wall at sensory-motor levels at 1 month; decreased thickness of the cortical wall at sensory-motor levels at p7; thicknesses of mz and subsequent l1 were unaltered at e18, p7, and p30
Description: Tbr1 and bcl11b-expressing deep layers extended superficially; enlargement of l5; thinning of rorβ and cux1-expressing layers 2â??4, which were shifted superficially; no change in numbers and laminar distribution of cpn subtypes in s1 at 1 month; superficial shift at p7
Description: Somatic volumes of l4 and l5 cpns were not significantly altered; more cells had elongated morphologies and increased overall areas and perimeters, typical of the multipolar-to-bipolar transition
Description: Excessive radial migration at e13.5-18.5; excess migration maintained at p7; pro-migratory effect of neurod2 deletion is generalized to other cpn subtypes; over-migration already occurs at 2 days post-electroporation when cells had not started terminal translocation yet
Description: No change in basal spine density at p30 and p120; apical spine density in cpns decreased at p30 but increased at p120; early onset; no change in spine density in other cpns
Description: Abnormal gene expression levels (gse110491); upregulation of voltage-gated ion channel, cell projection morphogenesis and chemical synaptic transmission; among dex asd genes, 8 were sfari score 1 and 25 sfari score 2â??3
Description: 11 dex genes representative of different expression profiles and disease associations (kcnh1 and cdh8 with expected l2/3 enrichment, kcnq5 and htr2a with l5 enrichment, scn4b, kcnk4, scn8a, scn1a, cacna1c, and grin2b with l2-6 enrichment) showed abnormal expression level i
Description: Thicknesses of mz and subsequent l1 were unaltered; iz and lower cp showed the strongest reductions in electroporated cell proportions in e13-e18 electroporated brains
Description: Excessive radial migration; no presence of ectopic neurons in mz; over-migration already occurs at 2 days post-electroporation when cells had not started terminal translocation yet
Description: 11 dex genes representative of different expression profiles and disease associations (kcnh1 and cdh8 with expected l2/3 enrichment, kcnq5 and htr2a with l5 enrichment, scn4b, kcnk4, scn8a, scn1a, cacna1c, and grin2b with l2-6 enrichment) showed an expression level in het mice that was either intermediate between wt and ko or undistinguishable to the ko level
