HGNC Approved Gene Symbol: NWD1
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:16,719,847-16,817,963 (from NCBI)
NWD1 contributes to the androgen receptor (AR; 313700) signaling pathway and is involved in axonal growth (summary by Yang et al., 2019).
Correa et al. (2014) stated that the NWD1 protein contains 1,358 amino acids and has a calculated molecular mass of 150.8 kD. NWD1 has an N-terminal WD repeat domain of about 40 amino acids, followed by a NACHT domain, a spacer region, 10 tandem WD repeats, another spacer, 2 additional WD repeats, and a short C-terminal tail. Quantitative PCR analysis detected NWD1 expression in most of 48 human tissues examined, with highest expression in prostate, followed by testis, retina, trachea, optic nerve, pituitary, and lung. Epitope-tagged NWD1 was expressed in the cytosol of transfected HEK293T cells.
Correa et al. (2014) identified enrichment of SRY (480000) sites in the promoter region of the NWD1 gene. PCR analysis showed induction of NWD1 expression in transfected HEK293T and PPC-1 prostatic carcinoma cells by SRY and the related transcription factor SOX9 (608160). Knockdown of NWD1 expression via lentiviral-based gene silencing dramatically reduced viability in androgen-responsive LNCaP prostate cancer cells. Silencing of NWD1 in LNCaP cells abrogated androgen-dependent reporter activity. Silencing of NWD1 also reduced expression of PDEF (SPDEF; 608144) in several human cell lines and may have had a minor effect in reducing activation of NF-kappa-B (see 164011). NWD1 expression was elevated during prostate cancer pathogenesis or progression.
By Western blot and immunostaining analyses, Yang et al. (2019) showed that NWD1 was expressed in excitatory synapses and that its expression was upregulated in brain tissue of seizure-induced mice and patients with temporal lobe epilepsy (TLE). Knockdown of Nwd1 weakened glutamatergic synaptic transmission in hippocampal pyramidal neurons of mice. Decreased Nwd1 decreased Glun2b (GRIN2B; 138252)-dependent excitatory postsynaptic currents in mouse hippocampal pyramidal neurons by altering phosphorylation of Glun2b at tyr1472. Moreover, decreased Nwd1 also alleviated neuronal hyperexcitability in hippocampal pyramidal neurons. These results, combined with the fact that phosphorylation of GLUN2B regulates trafficking and synaptic localization of N-methyl-D-aspartate (NMDA) receptors, suggested that NWD1 downregulation produces a long-lasting decrease in spontaneous firing of hippocampal pyramidal neurons due to the weakness of postsynaptic NMDA receptor function. In agreement, silencing Nwd1 reduced acute seizure severity in mice in vivo.
Correa et al. (2014) determined that the NWD1 gene has 19 exons and spans about 98 kb.
Correa et al. (2014) stated that the NWD1 gene maps to chromosome 19p13.11.
Correa, R. G., Krajewska, M., Ware, C. F., Gerlic, M., Reed, J. C. The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling. Oncotarget 5: 1666-1682, 2014. [PubMed: 24681825] [Full Text: https://doi.org/10.18632/oncotarget.1850]
Yang, Q., Huang, Z., Luo, Y., Zheng, F., Hu, Y., Liu, H., Zhu, S., He, M., Xu, D., Li, Y., Yang, M., Yang, Y., Wei, X., Gao, X., Wang, W., Ma, J., Ma, Y., Wang, X., Wang, Q. Inhibition of Nwd1 activity attenuates neuronal hyperexcitability and GluN2B phosphorylation in the hippocampus. EBioMedicine 47: 470-483, 2019. [PubMed: 31474551] [Full Text: https://doi.org/10.1016/j.ebiom.2019.08.050]