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HGNC Approved Gene Symbol: NAB2
Cytogenetic location: 12q13.3 Genomic coordinates (GRCh38): 12:57,089,114-57,095,476 (from NCBI)
Svaren et al. (1996) isolated a cDNA encoding NGFIA-binding protein-2 (NAB2) by screening a human brain cDNA library with a mouse genomic Nab2 probe and by 5-prime RACE. NAB2 is highly related to NAB1 (600800), which represses the transcriptional activity of both EGR1 (128990) and EGR2 (129010), zinc finger transcription factors encoded by immediate-early genes, and interacts with a 34-amino acid inhibitory region, named the R1 domain, contained in EGR1. Svaren et al. (1996) demonstrated that NAB2 can repress the transcriptional activity of both EGR1 and EGR2 in vitro. NAB2 is a 525-amino acid protein that differs from mouse Nab2 by 25 amino acids. Mouse Nab2 shows high homology to mouse Nab1 within 2 domains of approximately 100 amino acids each, called the Nab conserved domain-1 (NCD1) and NCD2. Apart from these 2 blocks of homology, the sequences of Nab1 and Nab2 have diverged considerably. Using the yeast 2-hybrid system, Svaren et al. (1996) showed that the NCD1 of Nab2 interacts specifically with the R1 domain of EGR1. Northern blotting of RNA isolated from various adult mouse tissues showed that Nab2 is most highly expressed in the brain and thymus, with significant expression also in the spleen, kidney, heart, and testes; there is little expression in the liver. Northern and Western blotting indicated that Nab2 expression is regulated by some of the same stimuli that induce EGR1 expression. Immunohistochemical analysis demonstrated that Nab2 is principally localized in the nucleus.
Svaren et al. (1996) determined that the Nab2 gene contains 7 exons. The authors detected an alternatively spliced NAB2 transcript that lacks exon 3, resulting in a frameshift and the production of a truncated protein. This truncated form of NAB2, which lacks the C-terminal portion of NCD2, is not localized to the nucleus and cannot repress EGR1 activity.
Svaren et al. (1996) mapped the human NAB2 gene to 12q13.3-q14.1 by fluorescence in situ hybridization.
Svaren et al. (1997) found that the NAB2 gene is situated unusually close to the STAT6 (601512) gene, with their coding regions separated by 1,852 bp. These genes are transcribed in an antiparallel direction, and the 3-prime ends of their mRNAs overlap by 58 bp. This overlap occurs within a 78-bp sequence that is perfectly conserved between human and mouse. A motif that confers rapid degradation to mRNAs is present within this conserved region. Since NAB2 is closely linked to both STAT6 and STAT2 (600556), and NAB1 is closely linked to STAT1 (600555) and STAT4 (600558), Svaren et al. (1997) suggested that chromosomal duplications simultaneously created new members of both the NAB and STAT families.
Svaren et al. (1997) mapped the mouse Nab2 gene to the distal region of chromosome 10 by interspecific backcross analysis.
NAB2/STAT6 Gene Fusion in Solitary Fibrous Tumors
Using whole-exome sequencing, Chmielecki et al. (2013) identified fusion of the NAB2 and STAT6 (601512) genes in 7 of 17 solitary fibrous tumors (SFTs). Analysis in 53 tumors confirmed the presence of 7 variants of this fusion transcript in 29 tumors (55%). Fusion analysis of approximately 713 unique tumor-normal pairs from 5 tumor types did not identify any fusions involving these genes, suggesting that the NAB2/STAT6 fusion may be unique to SFTs.
Following the identification of a gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 in a recurrent SFT, Robinson et al. (2013) identified a NAB2/STAT6 fusion gene in all of 51 SFTs using transcriptome sequencing and RT-PCR combined with capillary sequencing. The NAB2/STAT6 fusion was present regardless of the anatomical site of origin or malignant versus benign status. Expression of NAB2/STAT6 fusion protein was confirmed in SFTs. The predicted fusion products harbored the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2/STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR responsive genes. Proliferation could be inhibited by small interfering RNA (siRNA) knockdown of EGR1 expression. Robinson et al. (2013) concluded their studies established the NAB2/STAT6 fusion as the defining driver mutation of SFT and provided an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator.
Le et al. (2005) found that mice lacking either Nab1 or Nab2 were produced at the expected mendelian ratios and were overtly normal. However, mice lacking both Nab proteins survived no later than the third postnatal week. Nab1/Nab2 double-null mice were runted and showed labored breathing, weakness, uncoordinated movements, and severe tremors, similar to Egr2-null mice. Double-null mice did not show hindbrain segmentation deficits, which were seen in Egr2-null mice. Examination of peripheral nerves of double-null mice showed a defect in myelination, with Schwann cell development arrested at the promyelinating stage despite elevated Egr2 expression. As observed for Egr2, Nab proteins were necessary for Schwann cells to exit the cell cycle and generate a myelin-specific gene profile. Le et al. (2005) concluded that the EGR2/NAB protein complex in peripheral nerves is a key regulator of the Schwann cell myelination program.
Chmielecki, J., Crago, A. M., Rosenberg, M., O'Connor, R., Walker, S. R., Ambrogio, L., Auclair, D., McKenna, A., Heinrich, M. C., Frank, D. A., Meyerson, M. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nature Genet. 45: 131-135, 2013. [PubMed: 23313954] [Full Text: https://doi.org/10.1038/ng.2522]
Le, N., Nagarajan, R., Wang, J. Y. T., Svaren, J., LaPash, C., Araki, T., Schmidt, R. E., Milbrandt, J. Nab proteins are essential for peripheral nervous system myelination. Nature Neurosci. 8: 932-940, 2005. [PubMed: 16136673] [Full Text: https://doi.org/10.1038/nn1490]
Robinson, D. R., Wu, Y.-M., Kalyana-Sundaram, S., Cao, X., Lonigro, R. J., Sung, Y.-S., Chen, C.-L., Zhang, L., Wang, R., Su, F., Iyer, M. K., Roychowdhury, S., and 9 others. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nature Genet. 45: 180-185, 2013. [PubMed: 23313952] [Full Text: https://doi.org/10.1038/ng.2509]
Svaren, J., Apel, E. D., Simburger, K. S., Jenkins, N. A., Gilbert, D. J., Copeland, N. A., Milbrandt, J. The Nab2 and Stat6 genes share a common transcription termination region. Genomics 41: 33-39, 1997. [PubMed: 9126479] [Full Text: https://doi.org/10.1006/geno.1997.4609]
Svaren, J., Sevetson, B. R., Apel, E. D., Zimonjic, D. B., Popescu, N. C., Milbrandt, J. NAB2, a corepressor of NGFI-A (Egr-1) and Krox20, is induced by proliferative and differentiative stimuli. Molec. Cell. Biol. 16: 3545-3553, 1996. [PubMed: 8668170] [Full Text: https://doi.org/10.1128/MCB.16.7.3545]