Alternative titles; symbols
HGNC Approved Gene Symbol: NINJ1
Cytogenetic location: 9q22.31 Genomic coordinates (GRCh38): 9:93,121,496-93,134,251 (from NCBI)
The NINJ1 gene encodes ninjurin, a protein that is upregulated after nerve injury both in dorsal root ganglion neurons and in Schwann cells. It demonstrates properties of a homophilic adhesion molecule and promotes neurite outgrowth from primary cultured dorsal root ganglion neurons (Araki and Milbrandt, 1996).
Araki and Milbrandt (1996) cloned the ninjurin gene (NINJ1) from human and rat and suggested that it plays a role in nerve regeneration and in the formation and function of other tissues.
Araki et al. (1997) found that ninjurin is widely expressed in both adult and embryonic tissues, primarily those of epithelial origin. They used aggregation assays to demonstrate that ninjurin-mediated adhesion requires divalent cations and is an energy-dependent process. The critical domain for ninjurin-mediated homophilic adhesion was localized to an 11-residue region between pro26 and asn37 by mutagenesis and by employing synthetic oligopeptides as competitive inhibitors of ninjurin-mediated adhesion.
Chadwick et al. (1998) detected a 1.2-kb message for NINJ1 in all human tissues studied. The full-length sequence coded for a putative 152-amino acid protein with 89% identity to the rat ninjurin protein. Genomic characterization showed 4 exons covering less than 10 kb. They isolated the mouse homolog and showed that it has 98% amino acid identity to the rat protein.
Ifergan et al. (2011) found high expression of NINJ1 on human brain endothelial cells that make up the blood-brain barrier. Treatment with proinflammatory mediators resulted in increased NINJ1 expression on brain endothelial cells. NINJ1 was also expressed by cells of the myeloid lineage in human peripheral blood, particularly on CD14+ monocytes, CD68+ macrophages, and CD83+ myeloid dendritic cells. Ninj1 expression was also increased on inflammatory antigen-presenting cells (APCs) in the central nervous system of mice with experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS; 126200). These APCs appeared to be derived from the peripheral blood. Brain tissue from patients with MS showed increased NINJ1 expression on macrophages and dendritic cells within demyelinating lesions. In vitro studies showed that NINJ1 on human monocytes bound to primary cultures of brain endothelial cells within the transmigratory cup, suggesting that NINJ1 contributes to the transmigration of immune cells across the blood-brain barrier. Although blockade of NINJ1 decreased monocyte adhesion to endothelial cells, it did not alter the proliferation of helper T cells or cytokine production. However, treatment of EAE mice with an anti-Ninj1 antibody resulted in a reduction in clinical disease score, a reduction in infiltration of macrophages, dendritic cells, and APCs into the CNS, and a decrease in demyelination. The findings illustrated that NINJ1 has a functional role as an adhesion molecule that mediates the interaction between peripheral blood myeloid cells and endothelial cells that constitute the blood-brain barrier.
Exclusion Studies
Several genetic diseases of unknown etiology had been mapped to the 9q22 region, including hereditary sensory neuropathy type I (HSN1; 162400). However, Mandich et al. (1999) could demonstrate no abnormality of the NINJ1 gene in 17 unrelated patients with HSN type I, 2 patients with HSN type II (201300), and 10 normal controls, by SSCP and direct sequencing. All 3 exons and splice junctions of the gene were investigated.
Using fluorescence in situ hybridization, Araki et al. (1997) mapped the NINJ1 gene to 9q22. Chadwick et al. (1998) mapped the NINJ1 gene from a cDNA library enriched for transcripts from band 9q22. Chadwick et al. (1998) mapped the mouse gene to chromosome 13, a region that shows homology of synteny with human 9q22. The map position of the human gene was between D9S196 and D9S197. This placed the gene within the candidate regions for hereditary sensory neuropathy type I and the cancer predisposition syndrome multiple self-healing squamous epithelioma (MSSE; 132800).
Araki, T., Milbrandt, J. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth. Neuron 17: 353-361, 1996. [PubMed: 8780658] [Full Text: https://doi.org/10.1016/s0896-6273(00)80166-x]
Araki, T., Zimonjic, D. B., Popescu, N. C., Milbrandt, J. Mechanism of homophilic binding mediated by ninjurin, a novel widely expressed adhesion molecule. J. Biol. Chem. 272: 21373-21380, 1997. [PubMed: 9261151] [Full Text: https://doi.org/10.1074/jbc.272.34.21373]
Chadwick, B. P., Heath, S. K., Williamson, J., Obermayr, F., Patel, L., Sheer, D., Frischauf, A.-M. The human homologue of the ninjurin gene maps to the candidate region of hereditary sensory neuropathy type I (HSN1). Genomics 47: 58-63, 1998. [PubMed: 9465296] [Full Text: https://doi.org/10.1006/geno.1997.5084]
Ifergan, I., Kebir, H., Terouz, S., Alvarez, J. I., Lecuyer, M.-A., Gendron, S., Bourbonniere, L., Dunay, I. R., Bouthillier, A., Moumdjian, R., Fontana, A., Haqqani, A., Klopstein, A., Prinz, M., Lopez-Vales, R., Birchler, T., Prat, A. Role of ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions. Ann. Neurol. 70: 751-763, 2011. [PubMed: 22162058] [Full Text: https://doi.org/10.1002/ana.22519]
Mandich, P., Bellone, E., Di Maria, E., Pigullo, S., Pizzuti, A., Schenone, A., Soriani, S., Varese, A., Windebank, A. J., Ajmar, F. Exclusion of the ninjurin gene as a candidate for hereditary sensory neuropathies type I and type II. Am. J. Med. Genet. 83: 409-410, 1999. [PubMed: 10232753]