HGNC Approved Gene Symbol: NDN
Cytogenetic location: 15q11.2 Genomic coordinates (GRCh38): 15:23,685,400-23,687,305 (from NCBI)
Reasoning that additional imprinted genes may lie within the Prader-Willi syndrome (PWS; 176270) deletion interval 15q11-q13, MacDonald and Wevrick (1997) searched for transcribed sequences in the region between the 2 imprinted genes ZNF127 (MKRN3; 603856) and SNRPN (182279). An EST showed 99% sequence identity to the 3-prime end of a GenBank sequence (U35139), defined as 'a human necdin-related protein mRNA.' Mouse necdin (Ndn) was originally identified by Maruyama et al. (1991) as a protein encoded by a neural differentiation-specific mRNA, derived from embryonal carcinoma cells. The necdin protein was localized to the nuclei of postmitotic neurons and was expressed in almost all postmitotic neurons in the CNS from the beginning of neural differentiation and into adult life. MacDonald and Wevrick (1997) demonstrated that expression of the Ndn mouse gene and the NDN human gene is limited to the paternal allele, with highest levels of expression in brain and placenta. They suggested that loss of necdin gene expression may contribute to the disorder of brain development in individuals with PWS.
Jay et al. (1997) likewise cloned a human cDNA with close similarities to the mouse necdin gene. NDN displayed several characteristics of an imprinted locus, including allelic DNA methylation and an asynchronous DNA replication. Jay et al. (1997) found a complete lack of NDN expression in PWS brain and fibroblasts, indicating that the gene is expressed exclusively from the paternal allele in these tissues and suggesting a possible role of this gene in PWS.
Necdin is a growth suppressor expressed in virtually all postmitotic neurons in the brain. Nakada et al. (1998) isolated and characterized the human NDN gene and its promoter region. They found that NDN encodes a protein of 321 amino acids, 4 residues shorter than the mouse protein.
Watrin et al. (1997) demonstrated paternal-specific expression of the Ndn gene in mouse CNS and showed that paternal alleles display a differential methylation profile in the coding region.
Tcherpakov et al. (2002) found that necdin was expressed as a cytoplasmic protein in a rat neural precursor cell line.
Tcherpakov et al. (2002) found that the intracellular domain of nerve growth factor receptor (NGFR; 162010) interacted with necdin and Mageh1 (300548) in rodent neural tissue, and the interaction was enhanced by ligand stimulation. Rat neural precursor cells transfected with necdin or Mageh1 exhibited accelerated differentiation in response to NGF (see 162030).
Necdin and Magel2 (605283) are related proteins inactivated in PWS. Lee et al. (2005) demonstrated that necdin and Magel2 bound to and prevented proteasomal degradation of Fez1 (604825), which is implicated in axonal outgrowth and kinesin-mediated transport, and also bound to BBS4 (600374) protein in cotransfected cells. The interactions among necdin, Magel2, Fez1, and BBS4 occurred at or near centrosomes. Centrosomal or pericentriolar dysfunction has previously been implicated in BBS (209900) and may also be important in features of PWS that overlap with BBS, such as learning disabilities, hypogonadism, and obesity.
Miller et al. (2009) showed that necdin was not expressed in an immature, migratory gonadotropin-releasing hormone (GNRH1; 152760) neuronal cell line (GN11), but high levels were present in a mature GNRH neuronal cell line (GT1-7). Furthermore, overexpression of necdin activated GNRH transcription through cis elements bound by the homeodomain repressor Msx1 (142983) that were located in the enhancer and promoter of the GNRH1 gene, and knockdown of necdin expression reduced GNRH gene expression. Overexpression of Necdin relieved Msx repression of GNRH transcription through these elements and necdin coimmunoprecipitated with Msx from GNRH neuronal cells, indicating that necdin may activate GNRH gene expression by preventing repression of GNRH gene expression by Msx. Necdin was necessary for generation of the full complement of GNRH neurons during mouse development and extension of GNRH axons to the median eminence. As the NDN gene maps to the Prader-Willi syndrome candidate region and is highly expressed in mature hypothalamic neurons, Miller et al. (2009) hypothesized that lack of necdin during development may contribute to the hypogonadotrophic hypogonadal phenotype in individuals with PWS.
MacDonald and Wevrick (1997) determined that the mouse Ndn gene contains a single exon. Consistent with the observation that imprinted genes have few and small introns (Hurst et al., 1996), human NDN is contained within a single exon, like its mouse ortholog.
Nakada et al. (1998) identified CpG islands in a region of NDN extending from the proximal 5-prime flanking sequence to the protein-coding region. The 5-prime flanking sequence, which lacks canonical TATA and CAAT boxes, possessed a promoter activity in postmitotic neurons derived from murine embryonal carcinoma P19 cells. Methylation in vitro of HhaI CpG sites in the promoter region reduced transcriptional activity. These results suggested that the necdin gene is silenced through methylation of the CpG island encompassing its promoter region.
MacDonald and Wevrick (1997) concluded that the NDN gene is a single locus in proximal 15q, as determined by radiation hybrid mapping, localization of the appropriate PCR-amplified fragments to overlapping YACs, and absence in other YACs from the PWS deletion region. The mouse Ndn gene was mapped to chromosome 7 in a region of conserved synteny with human 15q11-q13 by MacDonald and Wevrick (1997) using genetic mapping in an interspecific backcross panel.
Jay et al. (1997) mapped the NDN gene to 15q11-q13 by fluorescence in situ hybridization (FISH), and confirmed the location by PCR analysis of DNA extracted from a panel of hamster/human somatic cell hybrids. Both approaches suggested that the NDN gene maps to 15q11-q13 but that a homologous gene or pseudogene maps to 12q21. Jay et al. (1997) also mapped NDN by hybridization to a YAC contig covering the PWS critical region. They suggested that NDN is located approximately 100 kb distal to ZNF127 and 1 to 1.5 Mb proximal to SNRPN.
By fluorescence in situ hybridization, Nakada et al. (1998) localized the NDN gene to chromosome 15q11.2-q12.
Watrin et al. (1997) established the localization of the mouse necdin gene in the region of mouse chromosome 7 showing conserved synteny to the human PWS region. By FISH, they demonstrated an asynchronous pattern of replication at the Ndn locus.
Tsai et al. (1999) prepared a null mutation in the mouse by deleting the coding region for Ndn, and transmitted the deletion to the germline. Mice with paternal deficiency and homozygous mice were viable. Northern blot analysis showed absence of Ndn expression in brain and liver of mice heterozygous for paternal deficiency. Mice of all genotypes were recovered at the predicted mendelian ratios at weaning following matings between heterozygotes. Mice of all genotypes, including homozygotes, were fertile and did not develop obesity up to 10 months of age. Behavioral studies had not yet been done; thus, any potential relationship to the mental retardation of PWS remained unknown.
To determine the possible contribution of Ndn to the Prader-Willi syndrome phenotype, Gerard et al. (1999) generated Ndn mutant mice. Heterozygous mice inheriting the mutated maternal allele were indistinguishable from their wildtype littermates. On the other hand, mice carrying a paternally inherited Ndn deletion allele demonstrated early postnatal lethality. Gerard et al. (1999) claimed this was the first example of a single gene being responsible for phenotypes associated with PWS.
Nicholls (1999) commented on the work of Gerard et al. (1999), which he called 'the latest episode of a seat-gripping saga.' He noted the discrepancy between the findings of Tsai et al. (1999) and those of Gerard et al. (1999). He further discussed other 'suspicious characters,' i.e., other genes that may be implicated in PWS, and suggested that several genes in the PWS region may affect the failure-to-thrive phenotype. He suggested that this aspect of the PWS story resembles the plot of 'Murder on the Orient Express' by Agatha Christie. The famed train transported a number of suspects, all of whom were eventually found to have had a part in the crime.
Muscatelli et al. (2000) produced mice deficient for necdin and suggested that postnatal lethality associated with loss of the paternal gene may vary depending on the strain. Viable necdin mutants showed a reduction in both oxytocin (167050)-producing and luteinizing hormone-releasing hormone (LHRH; 152760)-producing neurons in the hypothalamus; increased skin scraping activity; and improved spatial learning and memory. The authors proposed that underexpression of necdin is responsible for at least a subset of the multiple clinical manifestations of PWS.
Lee et al. (2005) demonstrated that morphologic abnormalities in axonal outgrowth and fasciculation manifested in several regions of the nervous system in Ndn-null mouse embryos, including axons of sympathetic, retinal ganglion cell, serotonergic, and catecholaminergic neurons. Lee et al. (2005) concluded that necdin mediates intracellular processes essential for neurite outgrowth and that loss of necdin may impinge on axonal outgrowth, and further suggested that loss of necdin may contribute to the neurologic phenotype of PWS. They speculated that codeletion of necdin and the related protein Magel2 (605283) may explain the lack of single gene mutations in PWS.
Gerard, M., Hernandez, L., Wevrick, R., Stewart, C. L. Disruption of the mouse necdin gene results in early post-natal lethality. Nature Genet. 23: 199-202, 1999. [PubMed: 10508517] [Full Text: https://doi.org/10.1038/13828]
Hurst, L. D., McVean, G., Moore, T. Imprinted genes have few and small introns. (Letter) Nature Genet. 12: 234-237, 1996. [PubMed: 8589711] [Full Text: https://doi.org/10.1038/ng0396-234]
Jay, P., Rougeulle, C., Massacrier, A., Moncla, A., Mattei, M.-G., Malzac, P., Roeckel, N., Taviaux, S., Lefranc, J.-L. B., Cau, P., Berta, P., Lalande, M., Muscatelli, F. The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nature Genet. 17: 357-360, 1997. [PubMed: 9354807] [Full Text: https://doi.org/10.1038/ng1197-357]
Lee, S., Walker, C. L., Karten, B., Kuny, S. L., Tennese, A. A., O'Neill, M. A., Wevrick, R. Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth. Hum. Molec. Genet. 14: 627-637, 2005. [PubMed: 15649943] [Full Text: https://doi.org/10.1093/hmg/ddi059]
MacDonald, H. R., Wevrick, R. The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum. Molec. Genet. 6: 1873-1878, 1997. [PubMed: 9302265] [Full Text: https://doi.org/10.1093/hmg/6.11.1873]
Maruyama, K., Usami, M., Aizawa, T., Yoshikawa, K. A novel brain-specific mRNA encoding nuclear protein (necdin) expressed in neurally differentiated embryonal carcinoma cells. Biochem. Biophys. Res. Commun. 178: 291-296, 1991. [PubMed: 2069569] [Full Text: https://doi.org/10.1016/0006-291x(91)91812-q]
Miller, N. L. G., Wevrick, R., Mellon, P. L. Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development. Hum. Molec. Genet. 18: 248-260, 2009. [PubMed: 18930956] [Full Text: https://doi.org/10.1093/hmg/ddn344]
Muscatelli, F., Abrous, D. N., Massacrier, A., Boccaccio, I., Le Moal, M., Cau, P., Cremer, H. Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum. Molec. Genet. 9: 3101-3110, 2000. [PubMed: 11115855] [Full Text: https://doi.org/10.1093/hmg/9.20.3101]
Nakada, Y., Taniura, H., Uetsuki, T., Inazawa, J., Yoshikawa, K. The human chromosomal gene for necdin, a neuronal growth suppressor, in the Prader-Willi syndrome deletion region. Gene 213: 65-72, 1998. [PubMed: 9630521] [Full Text: https://doi.org/10.1016/s0378-1119(98)00206-6]
Nicholls, R. D. Incriminating gene suspects, Prader-Willi style. Nature Genet. 23: 132-134, 1999. [PubMed: 10508501] [Full Text: https://doi.org/10.1038/13758]
Tcherpakov, M., Bronfman, F. C., Conticello, S. G., Vaskovsky, A., Levy, Z., Niinobe, M., Yoshikawa, K., Arenas, E., Fainzilber, M. The p75 neurotrophin receptor interacts with multiple MAGE proteins. J. Biol. Chem. 277: 49101-49104, 2002. [PubMed: 12414813] [Full Text: https://doi.org/10.1074/jbc.C200533200]
Tsai, T.-F., Armstrong, D., Beaudet, A. L. Necdin-deficient mice do not show lethality or the obesity and infertility of Prader-Willi syndrome. (Letter) Nature Genet. 22: 15-16, 1999. [PubMed: 10319852] [Full Text: https://doi.org/10.1038/8722]
Watrin, F., Roeckel, N., Lacroix, L., Mignon, C., Mattei, M.-G., Disteche, C., Muscatelli, F. The mouse necdin gene is expressed from the paternal allele only and lies in the 7C region of the mouse chromosome 7, a region of conserved synteny to the human Prader-Willi syndrome region. Europ. J. Hum. Genet. 5: 324-332, 1997. [PubMed: 9412790]