Alternative titles; symbols
HGNC Approved Gene Symbol: NEUROD1
SNOMEDCT: 44054006, 609573005; ICD10CM: E11;
Cytogenetic location: 2q31.3 Genomic coordinates (GRCh38): 2:181,668,295-181,680,517 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.3 | {Type 2 diabetes mellitus, susceptibility to} | 125853 | Autosomal dominant | 3 |
| Maturity-onset diabetes of the young 6 | 606394 | 3 |
Basic helix-loop-helix (bHLH) proteins are transcription factors involved in determining cell type during development. Lee et al. (1995) described a bHLH protein, termed NeuroD (for 'neurogenic differentiation') by them, that functions during neurogenesis. They cloned genes encoding the mouse and Xenopus NeuroD homologs and showed that they are expressed transiently in a subset of neurons in the central and peripheral nervous systems at the time of their terminal differentiation. They also found that ectopic expression of NeuroD in Xenopus embryos causes conversion of epithelial cells into neurons. See also NEUROD2 (601725) and NEUROD3 (601726).
Tamimi et al. (1996) cloned human NEUROD from a fetal brain cDNA library using the mouse gene as a probe. The predicted 357-amino acid polypeptide shares 97% identity with the mouse gene (100% identity in the bHLH region). They found that the NeuroD gene is identical to the hamster beta-2 gene that was cloned as a regulator of insulin (176730) gene transcription by Naya et al. (1995).
Naya et al. (1995) demonstrated that NEUROD1, following its heterodimerization with the ubiquitous helix-loop-helix HLH protein E47 (see 147141), regulates insulin gene expression by binding to a critical E-box motif on the insulin promoter.
Yan and Wang (2004) used engrailed-mediated active repression, antisense oligonucleotides, and small interfering RNA (siRNA) to attenuate neuroD expression and function in embryonic chick retinas. Chick embryos infected with retroviruses expressing an active repression construct exhibited severe photoreceptor deficits. The outer nuclear layer of the retina was no longer a contiguous structure, but became fragmented with regions that contained few or no photoreceptor cells. Photoreceptor deficiency was evident even before the retina became laminated, suggesting that active repression of neuroD may have affected photoreceptor genesis. No deficiency was observed in other types of retinal cells. Anti-neuroD antibody specifically labeled the nuclei of the outer nuclear layer. The data suggested a specific and essential role for neuroD in photoreceptor formation in the chick retina.
Pang et al. (2011) showed that POU3F2 (600494), ASCL1 (100790), and MYT1L (613084) can generate functional neurons from human pluripotent stem cells as early as 6 days after transgene activation. When combined with NEUROD1, these factors could also convert fetal and postnatal human fibroblasts into induced neuronal cells showing typical neuronal morphologies and expressing multiple neuronal markers, even after downregulation of the exogenous transcription factors. Importantly, the vast majority of human induced neuronal cells were able to generate action potentials and many matured to receive synaptic contacts when cocultured with primary mouse cortical neurons. Pang et al. (2011) concluded that nonneuronal human somatic cells, as well as pluripotent stem cells, can be converted directly into neurons by lineage-determining transcription factors.
By interspecific backcross, Tamimi et al. (1996) mapped the mouse Neurod gene to chromosome 2. By fluorescence in situ hybridization they mapped the human NEUROD gene to chromosome 2q32. The authors noted that the type I insulin-dependent diabetes locus IDDM7 (600321) maps to 2q31-q33 and that NEUROD is a potential candidate gene for that disorder.
Malecki et al. (1999) described 2 heterozygous mutations in NEUROD1 that were associated with the development of type II diabetes (125853). One is the missense mutation arg111-to-leu (601724.0001), which disrupts the DNA-binding domain and abolishes the E-box binding activity of NEUROD1. The second mutation, 206+C (601724.0002) gives rise to a truncated polypeptide lacking the C-terminal transactivation domain, a region that associates with the coactivators CBP (600140) and p300 (602700). The clinical profile of patients with the truncated NEUROD1 polypeptide was more severe and more suggestive of a MODY (see 606391), whereas that of patients with the arg111-to-leu mutation was more typical of type II diabetes mellitus.
Fajans et al. (2001) referred to the diabetes due to mutation in the NEUROD1 gene as maturity-onset diabetes of the young type 6 (MODY6; 606394).
Associations Pending Confirmation
For discussion of a possible association between retinitis pigmentosa and variation in the NEUROD1 gene, see 601724.0003.
Naya et al. (1997) demonstrated that mice homozygous for a targeted disruption of Neurod have abnormal pancreatic islet morphogenesis and overt diabetes due to inadequate expression of the insulin gene.
NeuroD is a homolog of the Drosophila 'atonal' gene that is widely expressed during development in the mammalian brain and pancreas. Although studies in Xenopus had suggested that NeuroD is involved in cellular differentiation, its function in the mammalian nervous system had not been determined. Liu et al. (2000) showed that mice homozygous for a deletion of the NeuroD gene failed to develop a granule cell layer within the dentate gyrus, one of the principal structures of the hippocampal formation. Using immunocytochemical markers in the deficient mice, the authors showed that the early cell populations in the dentate gyrus were present and appeared normally organized. The migration of dentate precursor cells in newly born granule cells from the neuroepithelium to the dentate gyrus remained intact. However, there was a dramatic defect in the proliferation of precursor cells once they reached the dentate, and a significant delay in the differentiation of granule cells. This led to malformation of the dentate granule cell layer and excess cell death. The homozygous-null mice exhibited spontaneous limbic seizures associated with electrophysiologic evidence of seizure activity in the hippocampus and cortex.
Liu et al. (2000) found that Neurod1-null mice exhibited behavioral abnormalities suggestive of an inner ear defect, including lack of responsiveness to sound, hyperactivity, head tilting, and circling. These defects were due to severe reduction of sensory neurons in the cochlear-vestibular ganglion (CVG) caused by delayed or defective delamination of CVG neuroblast precursors from the otic vesicle epithelium and enhanced apoptosis in the otic epithelium and in neurons that delaminate to form the CVG. Neurod1-null mice also showed defects in differentiation and patterning of the cochlear duct and sensory epithelium and loss of the dorsal cochlear nucleus.
In a family (family A) segregating type II diabetes mellitus (125853), Malecki et al. (1999) identified a G-to-T transversion in the NEUROD1 gene resulting in an arg-to-leu substitution at codon 111 (R111L). The mutation was located in the proximal basic portion of the basic helix-loop-helix (bHLH) domain, which is responsible for DNA binding. Arg111 is an invariant residue among members of the bHLH family. Of 6 carriers of this mutation, 4 had previously been diagnosed with diabetes and 2 had impaired glucose intolerance diagnosed at the time of examination. The average age of these 4 carriers at the time of diagnosis was 40 (range 30 to 59 years). One noncarrier at age 52 had diabetes treated by oral medication, and another noncarrier at age 65 had impaired glucose tolerance. These 2 individuals were deemed most likely to be phenocopies.
In a family (family B) segregating maturity-onset diabetes of the young (MODY6; 606394), Malecki et al. (1999) identified insertion of a cytosine residue in a polyC tract in codon 206 in exon 2 (designated 206+C) of the NEUROD1 gene, resulting in a frameshift and synthesis of a nonsense peptide from amino acid 205 to 242, followed by a premature stop codon. The mutant protein thus lacked the C-terminal third of the protein, which harbors the transactivation domain and interacts with the cellular coactivator p300. The mutation was identified in 7 previously diagnosed diabetics and in 2 nondiabetic individuals who were apparently nonpenetrants. The average age of the 7 carriers at the time of diagnosis was 31, with a range of 17 to 56 years. At the time of examination the diabetes was treated with diet, oral agents, or insulin. All patients had low serum insulin levels, and 2 whose diabetes was treated with insulin had undetectable serum C peptide. The more severe clinical profile was thought to resemble a MODY phenotype.
This variant is classified as a variant of unknown significance because its contribution to retinitis pigmentosa (RP; see 268000) has not been confirmed.
In a brother and sister with late-onset RP, who were born to first-cousin Han Chinese parents and were negative for mutation in 186 known retinal disease-causing genes, Wang et al. (2015) performed whole-exome capture and identified homozygosity for a c.724G-A transition in the NEUROD1 gene, resulting in a val242-to-ile (V242I) substitution at a highly conserved residue. Sanger sequencing confirmed the mutation, which was present in heterozygosity in their unaffected father and 2 unaffected sibs. The 33-year-old male proband reported 15 years of night blindness and 8 years of progressively decreasing visual acuity. Fundus examination showed bone-spicule pigmentation in the midperiphery with attenuated retinal vessels, and optical coherence tomography showed increased retinal thickness in the macular region, with discontinuous inner/outer segment junction signal and loss of the foveal pit. Visual field testing showed symmetrical loss of upper and temporal visual fields, with conserved central vision in both eyes. Electroretinography was consistent with widespread rod and cone degeneration. The proband's 40-year-old sister, who had had night blindness since childhood, was found to have severe subcapsular cataracts bilaterally on slit-lamp examination. She also exhibited diffuse retinal pigment epithelial and choroidal atrophy, with characteristic bone-spicule pigmentation in the midperiphery. A vitreous membrane was observed in the right eye. Neither patient had systemic abnormalities; specifically, they both had normal HbA1c levels, and neither had any neurologic symptoms. No functional analysis of the variant was reported, but Wang et al. (2015) noted that the RP phenotype was consistent with previously reported knockout mouse models showing that Neurod1 is required for survival of adult photoreceptor cells and that loss of Neurod1 causes progressive retinal degeneration (Pennesi et al., 2003; Ochocinska et al., 2012).
Fajans, S. S., Bell, G. I., Polonsky, K. S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. New Eng. J. Med. 345: 971-980, 2001. [PubMed: 11575290] [Full Text: https://doi.org/10.1056/NEJMra002168]
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]
Liu, M., Pereira, F. A., Price, S. D., Chu, M., Shope, C., Himes, D., Eatock, R. A., Brownell, W. E., Lysakowski, A., Tsai, M.-J. Essential role of BETA2/NeuroD1 in development of the vestibular and auditory systems. Genes Dev. 14: 2839-2854, 2000. [PubMed: 11090132] [Full Text: https://doi.org/10.1101/gad.840500]
Liu, M., Pleasure, S. J., Collins, A. E., Noebels, J. L., Naya, F. J., Tsai, M.-J., Lowenstein, D. H. Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy. Proc. Nat. Acad. Sci. 97: 865-870, 2000. Note: Erratum: Proc. Nat. Acad. Sci. 97: 5679 only, 2000. [PubMed: 10639171] [Full Text: https://doi.org/10.1073/pnas.97.2.865]
Malecki, M. T., Jhala, U. S., Antonellis, A., Fields, L., Doria, A., Orban, T., Saad, M., Warram, J. H., Montminy, M., Krolewski, A. S. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nature Genet. 23: 323-328, 1999. [PubMed: 10545951] [Full Text: https://doi.org/10.1038/15500]
Naya, F. J., Huang, H.-P., Qiu, Y., Mutoh, H., DeMayo, F. J., Leiter, A. B., Tsai, M.-J. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neurod-deficient mice. Genes Dev. 11: 2323-2334, 1997. [PubMed: 9308961] [Full Text: https://doi.org/10.1101/gad.11.18.2323]
Naya, F. J., Stellrecht, C. M., Tsai, M. J. Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dev. 9: 1009-1019, 1995. [PubMed: 7774807] [Full Text: https://doi.org/10.1101/gad.9.8.1009]
Ochocinska, M. J., Munoz, E. M., Veleri, S., Weller, J. L., Coon, S. L., Pozdeyev, N., Iuvone, P. M., Goebbels, S., Furukawa, T., Klein, D. C. NeuroD1 is required for survival of photoreceptors but not pinealocytes: results from targeted gene deletion studies. J. Neurochem. 123: 44-59, 2012. [PubMed: 22784109] [Full Text: https://doi.org/10.1111/j.1471-4159.2012.07870.x]
Pang, Z. P., Yang, N., Vierbuchen, T., Ostermeier, A., Fuentes, D. R., Yang, T. Q., Citri, A., Sebastiano, V., Marro, S., Sudhof, T. C., Wernig, M. Induction of human neuronal cells by defined transcription factors. Nature 476: 220-223, 2011. [PubMed: 21617644] [Full Text: https://doi.org/10.1038/nature10202]
Pennesi, M. E., Cho, J.-H., Yang, Z., Wu, S. H., Zhang, J., Wu, S. M., Tsai, M.-J. BETA2/NeuroD1 null mice: a new model for transcription factor-dependent photoreceptor degeneration. J. Neurosci. 23: 453-461, 2003. [PubMed: 12533605] [Full Text: https://doi.org/10.1523/JNEUROSCI.23-02-00453.2003]
Tamimi, R., Steingrimsson, E., Copeland, N. G., Dyer-Montgomery, K., Lee, J. E., Hernandez, R., Jenkins, N. A., Tapscott, S. J. The NEUROD gene maps to human chromosome 2q32 and mouse chromosome 2. Genomics 34: 418-421, 1996. [PubMed: 8786144] [Full Text: https://doi.org/10.1006/geno.1996.0306]
Wang, F., Li, H., Xu, M., Li, H., Zhao, L., Yang, L., Zaneveld, J. E., Wang, K., Li, Y., Sui, R., Chen, R. A homozygous missense mutation in NEUROD1 is associated with nonsyndromic autosomal recessive retinitis pigmentosa. Invest. Ophthal. Vis. Sci. 56: 150-155, 2015.
Yan, R.-T., Wang, S.-Z. Requirement of neuroD for photoreceptor formation in the chick retina. Invest. Ophthal. Vis. Sci. 45: 48-58, 2004. [PubMed: 14691153] [Full Text: https://doi.org/10.1167/iovs.03-0774]