Alternative titles; symbols
HGNC Approved Gene Symbol: NEUROG1
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:135,534,282-135,535,964 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.1 | Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay | 620469 | Autosomal recessive | 3 |
The NEUROG1 gene encodes a basic helix-loop-helix (bHLH) transcription factor essential for the formation of proximal cranial sensory nerve ganglia and neurons (summary by Dupont et al., 2021; Sheth et al., 2023).
Basic helix-loop-helix (bHLH) proteins are transcription factors involved in determining cell type during development. Lee et al. (1995) described a bHLH protein, which they termed NeuroD (neurogenic differentiation), that functions during neurogenesis. McCormick et al. (1996) described the cloning and characterization of 2 additional NEUROD genes, NEUROD2 (601725) and NEUROD3. The latter gene has also been designated NEUROG1 and NGN1. 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 NeuroD3 is expressed transiently during embryonic development, with the highest level of expression between days 10 and 12.
The NEUROG1 gene contains 1 exon (summary by Dupont et al., 2021).
Sun et al. (2001) found that in addition to inducing neurogenesis, NGN1 inhibits the differentiation of neural stem cells into astrocytes. While NGN1 promotes neurogenesis by functioning as a transcriptional activator, NGN1 inhibits astrocyte differentiation by sequestering the CREB-binding protein (CBP; 600140)/SMAD1 (601595) transcription complex away from astrocyte differentiation genes and by inhibiting the activation of STAT transcription factors (600555) necessary for gliogenesis. Thus, 2 distinct mechanisms are involved in the activation and suppression of gene expression during cell-fate specification by NGN1.
Ma et al. (1999) presented a detailed analysis of Neurod3 and Neurog2 (606624) expression during neural crest migration and early dorsal root gangliogenesis in wildtype and various neurogenin mutant mouse embryos. They concluded that Neurod3 and Neurog2 control 2 distinct phases of neurogenesis that generate different classes of sensory neurons.
Tamimi et al. (1997) mapped the NEUROD3 gene to chromosome 5q23-q31 by fluorescence in situ hybridization. They mapped the mouse homolog to chromosome 13.
In a 12-year-old boy, born of consanguineous Middle Eastern parents, with congenital cranial dysinnervation disorder with absent corneal reflex and developmental delay (CCDDRD; 620469), Yavarna et al. (2015) identified a homozygous missense mutation in the NEUROG1 gene (R116L; 601726.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Familial segregation was not reported. Functional studies of the variant and studies of patient cells were not performed.
In a 12-year-old Portuguese boy with CCDDRD, Dupont et al. (2021) identified a homozygous nonsense mutation in the NEUROG1 gene (E68X; 601726.0002). The mutation, which was found by trio-based exome sequencing, segregated with the disorder in the family. The authors suggested that the mutation most likely led to production of a truncated protein with a loss of function. Functional studies of the variant and studies of patient cells were not performed.
In 2 sisters, born of Indian parents, with CCDDRD, Sheth et al. (2023) identified a homozygous frameshift mutation in the NEUROG1 gene (601726.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the authors suggested that an abnormal protein could be produced. Sheth et al. (2023) noted that all reported NEUROG1 mutations affected the bHLH domain, likely disrupting its function.
Ma et al. (1998) generated Ngn1-deficient mice, which failed to generate the proximal subset of cranial sensory neurons. They concluded that Ngn1 is required for the activation of a cascade of downstream bHLH factors and functions in the determination of neuronal precursors.
Using immunocytochemistry, nerve tract tracing, and electron microscopy, Ma et al. (2000) characterized an abnormal inner ear phenotype in the Ngn1-null mutants generated by Ma et al. (1998). In summary, Ngn1-null mutants lack differentiated inner ear sensory neurons. Ma et al. (2000) hypothesized that efferent and autonomic nerve fibers are lost secondarily to the absence of afferent nerve fibers. The Ngn1 mutant ears develop smaller sensory epithelia with hair cells that are morphologically normal but disorganized and reduced in number. Ma et al. (2000) concluded that Ngn1 is essential for development of the inner ear sensory neurons.
Using in situ hybridization and immunofluorescence, Gowan et al. (2001) compared the embryonic expression of Mash1 (ASCL1; 100790), Math1 (ATOH1; 601461), and Ngn1 in mouse and concluded that they define 3 distinct, nonoverlapping populations of neural progenitor cells in the dorsal neural tube. They used reporter gene constructs in transgenic mice to identify a neural-specific enhancer sequence 5-prime of the Ngn1 coding region that directs gene expression to a subset of the normal Ngn1 expression domain. Combining their expression data with loss- and gain-of-function experiments in mouse and chick, Gowan et al. (2001) hypothesized that Atoh1 and the neurogenin factors repress each other's expression, resulting in progenitors expressing only one bHLH factor. Ngn1 progenitors give rise to a subset of dorsal cells that coexpress Lim1/2 (LHX1, 601999; LHX2, 603759) and Brn3a (POU4F1; 601632). Either Ngn1 or Neurog2 is required for these cells to form. Gowan et al. (2001) concluded that although Ngn1, Neurog2, and Atoh1 appear to have redundant functions in inducing neurogenesis, they have distinct roles in specifying neuronal cell subtype in the dorsal neural tube.
In a 12-year-old boy, born of consanguineous Middle Eastern parents, with congenital cranial dysinnervation disorder with absent corneal reflex and developmental delay (CCDDRD; 620469), Yavarna et al. (2015) identified a homozygous c.347G-T transversion in the NEUROG1 gene, resulting in an arg116-to-leu (R116L) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Familial segregation was not reported. Functional studies of the variant and studies of patient cells were not performed. Sheth et al. (2023) noted that the R116L mutation lies within the bHLH domain and likely disrupts its function. Clinical details were limited, but sensorineural deafness was not noted in this patient.
In a 12-year-old Portuguese boy with congenital cranial dysinnervation disorder with absent corneal reflex and developmental delay (CCDDRD; 620469), Dupont et al. (2021) identified a homozygous c.202G-T transversion (c.202G-T, NM_006161.2) in the NEUROG1 gene, resulting in a glu68-to-ter (E68X) substitution. The mutation, which was found by trio-based exome sequencing, segregated with the disorder in the family. It was not present in homozygosity in gnomAD. The authors suggested that the mutation most likely led to production of a truncated protein with a loss of function. Functional studies of the variant and studies of patient cells were not performed. Sheth et al. (2023) noted that the E68X mutation lies before the bHLH domain, likely disrupting its function. The patient also had profound sensorineural deafness, hypoplasia and malformations of the cochlea, and agenesis of CN V and CN VIII.
In 2 sisters, born of Indian parents, with congenital cranial dysinnervation disorder with absent corneal reflex and developmental delay (CCDDRD; 620469), Sheth et al. (2023) identified a homozygous 4-bp duplication (c.228_231dup, ENST00000314744.4) in exon 1 of the NEUROG1 gene, predicted to result in a frameshift and premature termination (Thr78ProfsTer122) in the bHLH domain, likely disrupting its function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The authors noted that the mutation may not result in nonsense-mediated mRNA decay and hypothesized that an abnormal protein could be produced. The patients also had hearing loss and malformations of the cochlea.
Dupont, J., Vieira, J. P., Tavares, A. L. T., Conceicao, C. R., Khan, S., Bertoli-Avella, A. M., Sousa, A. B. Adding evidence to the role of NEUROG1 in congenital cranial dysinnervation disorders. Clin. Genet. 99: 588-593, 2021. [PubMed: 33439489] [Full Text: https://doi.org/10.1111/cge.13922]
Gowan, K., Helms, A. W., Hunsaker, T. L., Collisson, T., Ebert, P. J., Odom, R., Johnson, J. E. Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 31: 219-232, 2001. [PubMed: 11502254] [Full Text: https://doi.org/10.1016/s0896-6273(01)00367-1]
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]
Ma, Q., Anderson, D. J., Fritzsch, B. Neurogenin 1 null mutant ears develop fewer, morphologically normal hair cells in smaller sensory epithelia devoid of innervation. J. Assoc. Res. Otolaryng. 1: 129-143, 2000. Note: Erratum: J. Assoc. Res. Otolaryng. 1: 326 only, 2000. [PubMed: 11545141] [Full Text: https://doi.org/10.1007/s101620010017]
Ma, Q., Chen, Z., del Barco Barrantes, I., de la Pompa, J. L., Anderson, D. J. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron 20: 469-482, 1998. [PubMed: 9539122] [Full Text: https://doi.org/10.1016/s0896-6273(00)80988-5]
Ma, Q., Fode, C., Guillemot, F., Anderson, D. J. Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia. Genes Dev. 13: 1717-1728, 1999. [PubMed: 10398684] [Full Text: https://doi.org/10.1101/gad.13.13.1717]
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]
Sheth, F., Shah, J., Patel, K., Patel, D., Jain, D., Sheth, J., Sheth, H. A novel case of two siblings harbouring homozygous variant in the NEUROG1 gene with autism as an additional phenotype: a case report. BMC Neurol. 23: 20, 2023. [PubMed: 36647078] [Full Text: https://doi.org/10.1186/s12883-023-03065-1]
Sun, Y., Nadal-Vicens, M., Misono, S., Lin, M. Z., Zubiaga, A., Hua, X., Fan, G., Greenberg, M. E. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104: 365-376, 2001. [PubMed: 11239394] [Full Text: https://doi.org/10.1016/s0092-8674(01)00224-0]
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]
Yavarna, T., Al-Dewik, N., Al-Mureikhi, M., Ali, R., Al-Mesaifri, F., Mahmoud, L., Shahbeck, N., Lakhani, S., AlMulla, M., Nawaz, Z., Vitazka, P., Alkuraya, F. S., Ben-Omran, T. High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders. Hum. Genet. 134: 967-980, 2015. [PubMed: 26077850] [Full Text: https://doi.org/10.1007/s00439-015-1575-0]