HGNC Approved Gene Symbol: NEUROD2
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:39,603,768-39,607,920 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | Developmental and epileptic encephalopathy 72 | 618374 | Autosomal dominant | 3 |
The NEUROD2 gene encodes a basic helix-loop-helix (bHLH) protein that is a transcription factor involved in central and peripheral nervous system development (summary by Sega et al., 2019).
Lee et al. (1995) described a bHLH protein, NEUROD (NEUROD1; 601724), that functions during neurogenesis. McCormick et al. (1996) described the cloning and characterization of 2 additional NEUROD genes, NEUROD2 and NEUROD3 (601726). Sequences for the mouse and human homologs were presented. NEUROD2 shows a high degree of homology to the bHLH region of NEUROD, whereas NEUROD3 is more distantly related.
McCormick et al. (1996) found that mouse neuroD2 was initially expressed at embryonic day 11, with persistent expression in the adult nervous system. Similar to neuroD, neuroD2 appears to mediate neuronal differentiation.
Yang et al. (2009) found that the major mitotic E3 ubiquitin ligase Cdc20 (603618)-anaphase-promoting complex (Cdc20-APC; see ANAPC1, 608473) regulates presynaptic differentiation in primary postmitotic mammalian neurons and in the rat cerebellar cortex. Cdc20-APC triggered the degradation of the transcription factor NeuroD2 and thereby promoted presynaptic differentiation. The NeuroD2 target gene encoding complexin-2 (CPLX2; 605033), which acts locally at presynaptic sites, mediated the ability of NeuroD2 to suppress presynaptic differentiation. Yang et al. (2009) concluded that their findings defined a Cdc20-APC ubiquitin signaling pathway that governs presynaptic development.
Yoo et al. (2011) demonstrated that expression of miR9/9* (see 611186) and miR-124 (609327) in human fibroblasts induced their conversion into neurons, a process facilitated by NEUROD2. Further addition of neurogenic transcription factors ASCL1 (100790) and MYT1L (613084) enhanced the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without the aforementioned microRNAs was ineffective. Yoo et al. (2011) concluded that the genetic circuitry involving miR9-1 through miR9-3 and miR124 can have an instructive role in neural fate determination.
Tamimi et al. (1997) mapped human NEUROD2 to 17q12 by fluorescence in situ hybridization. They mapped the mouse homolog to chromosome 11.
In 2 unrelated children with developmental and epileptic encephalopathy-72 (DEE72; 618374), Sega et al. (2019) identified de novo heterozygous missense mutations in the NEUROD2 gene (E130Q, 601725.0001 and M134T, 601725.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. Both mutations occurred in the DNA-binding domain. Overexpression of wildtype Neurod2 in X. laevis induces nonneuronal cells to differentiate into neurons and promotes the ectopic expression of neurons expressing mature neural markers. In contrast, expression of the missense mutations into X. laevis resulted in impaired (M134T) or absent (E130Q) ectopic neurons compared to wildtype, suggesting a loss of function.
Ince-Dunn et al. (2006) found that Neurod2 -/- mice were born at a normal mendelian ratio, but most died between 4 to 5 weeks of age. Both Neurod2 -/- and Neurod2 +/- mice showed altered brain organization compared with wildtype littermates, including decreased brain size, slightly smaller and rounder hippocampus, and absence of corpus callosum. Thalamocortical axon terminals of Neurod2 -/- mice failed to segregate in the somatosensory cortex, and the postsynaptic barrel organization was disrupted. Synaptic transmission was defective at thalamocortical synapses in Neurod2 -/- mice, with reduced total excitatory synaptic currents in layer IV due to reduced contribution of AMPA receptors (see GR1AI; 138248) compared with NMDA receptors (see GRIN1; 138249).
Sega et al. (2019) found that knockdown of the Neurod2 orthologs in X. tropicalis tadpoles caused abnormal swimming behavior and seizures followed by periods of immobility.
In a 3.5-year-old girl with infantile epileptic encephalopathy-72 (DEE72; 618374), Sega et al. (2019) identified a de novo heterozygous c.388G-C transversion (c.388G-C, NM_006160.3) in the NEUROD2 gene, resulting in a glu130-to-gln (E130Q) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Expression of the E130Q mutations into X. laevis resulted in absent production of ectopic neurons compared to wildtype, suggesting a complete loss of function. At 5 months of age, the patient had onset of refractory infantile spasms associated with hypsarrhythmia on EEG.
In a 2.5-year-old boy with infantile epileptic encephalopathy-72 (DEE72; 618374), Sega et al. (2019) identified a de novo heterozygous c.401T-C transition (c.401T-C, NM_006160.3) in the NEUROD2 gene, resulting in a met134-to-thr (M134T) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Expression of the M134T mutation into X. laevis resulted in impaired production of ectopic neurons compared to wildtype, suggesting a partial loss of function. At 5 months of age, the patient had onset of refractory infantile spasms associated with hypsarrhythmia on EEG.
Ince-Dunn, G., Hall, B. J., Hu, S.-C., Ripley, B., Huganir, R. L., Olson, J. M., Tapscott, S. J., Ghosh, A. Regulation of thalamocortical patterning and synaptic maturation by NeuroD2. Neuron 49: 683-695, 2006. [PubMed: 16504944] [Full Text: https://doi.org/10.1016/j.neuron.2006.01.031]
Lee, J. E., Hollenberg, S. M., Snider, L., Turner, D. L., Lipnick, N., Weintraub, H. Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein. Science 268: 836-844, 1995. [PubMed: 7754368] [Full Text: https://doi.org/10.1126/science.7754368]
McCormick, M. B., Tamimi, R. M., Snider, L., Asakura, A., Bergstrom, D., Tapscott, S. J. neuroD2 and neuroD3: distinct expression patterns and transcriptional activation potentials within the neuroD gene family. Molec. Cell. Biol. 16: 5792-5800, 1996. [PubMed: 8816493] [Full Text: https://doi.org/10.1128/MCB.16.10.5792]
Sega, A. G., Mis, E. K., Lindsrom, K., Mercimek-Andrews, S., Ji, W., Cho, M. T., Juusola, J., Konstantino, M., Jeffries, L., Khokha, M. K., Lakhani, S. A. Do novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy. J. Med. Genet. 56: 113-122, 2019. [PubMed: 30323019] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105322]
Tamimi, R. M., Steingrimsson, E., Montgomery-Dyer, K., Copeland, N. G., Jenkins, N. A., Tapscott, S. J. NEUROD2 and NEUROD3 genes map to human chromosomes 17q12 and 5q23-q31 and mouse chromosomes 11 and 13, respectively. Genomics 40: 355-357, 1997. [PubMed: 9119405] [Full Text: https://doi.org/10.1006/geno.1996.4578]
Yang, Y., Kim, A. H., Yamada, T., Wu, B., Bilimoria, P. M., Ikeuchi, Y., de la Iglesia, N., Shen, J., Bonni, A. A Cdc20-APC ubiquitin signaling pathway regulates presynaptic differentiation. Science 326: 575-578, 2009. [PubMed: 19900895] [Full Text: https://doi.org/10.1126/science.1177087]
Yoo, A. S., Sun, A. X., Li, L., Shcheglovitov, A., Portmann, T., Li, Y., Lee-Messer, C., Dolmetsch, R. E., Tsien, R. W., Crabtree, G. R. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476: 228-231, 2011. [PubMed: 21753754] [Full Text: https://doi.org/10.1038/nature10323]