Alternative titles; symbols
HGNC Approved Gene Symbol: BRINP1
Cytogenetic location: 9q33.1 Genomic coordinates (GRCh38): 9:119,166,629-119,369,435 (from NCBI)
BRINP1 is a neural-specific protein that belongs to the BRINP family (Kawano et al., 2004).
The most frequent genetic alteration noted in both superficial papillary and invasive transitional cell carcinoma (TCC) of the bladder is loss of heterozygosity (LOH) at, or deletion of, chromosome arms 9q and/or 9p. On 9q, there are at least 3 common regions of LOH. Habuchi et al. (1997) localized one of these regions to 9q32-q33, within a single YAC of 840 kilobases. Habuchi et al. (1998) isolated a complete cDNA sequence from this region by a combination of EST identification, fetal brain library screening, and 5-prime RACE. The 3,158-bp DBCCR1 cDNA sequence contains an open reading frame encoding 761 amino acids with an estimated molecular mass of 88,869. The putative protein contains 7 potential N-glycosylation sites, 4 N-myristoylation sites, and 30 phosphorylation sites. Northern blot analysis showed that DBCCR1 is expressed as a single major band of 3.0 to 3.5 kb in multiple normal human tissues, including urothelium.
Kawano et al. (2004) cloned rat Brinp1, which encodes a predicted protein of 760 amino acids. BRINP1, BRINP2 (619359), and BRINP3 (618390) are highly conserved among human, mouse, and rat, with BRINP2 and BRINP3 more closely related than BRINP1. Human and rat BRINP1 share 99% amino acid identity. All 3 BRINP proteins have an N-terminal signal peptide. Northern blot, RT-PCR, and in situ hybridization showed that, similar to other Brinp family members, Brinp2 was expressed specifically in rodent nervous system in a developmentally regulated manner. Immunofluorescence analysis showed that fluorescence-tagged rat Brinp proteins localized to cytoplasm and granular structures overlapping with endoplasmic reticulum in NIH3T3 and PC12 cells.
Using RT-PCR analysis, Terashima et al. (2010) showed that expression of all 3 Brinp genes was not detectable in mouse embryonic stem (ES) cells. In ES cell-derived neural stem cells (NSCs), Brinp1 expression was not significantly induced, whereas Brinp2 and Brinp3 expression was slightly induced. Upon differentiation of ES-derived NSCs into neuronal cells, expression of all 3 Brinp genes was significantly induced with similar time course. Upon differentiation of ES-derived NSCs into astroglial cells, Brinp1 expression was slightly increased, whereas Brinp2 and Brinp3 expression was almost abolished.
Habuchi et al. (1998) found that the DBCCR1 gene contains 8 exons and demonstrated that the 5-prime end of the gene is located telomeric to the 3-prime end.
Habuchi et al. (1998) mapped the DBCCR1 gene to chromosome 9q32-q33.
Gross (2021) mapped the BRINP1 gene to chromosome 9q33.1 based on an alignment of the BRINP1 sequence (GenBank BC065196) with the genomic sequence (GRCh38).
Using Northern blot analysis, Habuchi et al. (1998) found that DBCCR1 mRNA expression was absent in 5 of 10 bladder cancer cell lines. Mutation analysis of the DBCCR1 coding region and Southern blot analysis detected neither somatic mutations nor gross genetic alterations in primary TCCs of the bladder. Methylation analysis of the CpG island at the 5-prime region of the gene and the induction of de novo expression by a demethylating agent indicated that this island might be a frequent target for hypermethylation and that hypermethylation-based silencing of the gene occurs in TCC.
By Northern and Western blot analysis, Wright et al. (2002) showed that transient transfection of SMPDL3A (610728) and DBCCR1 in bladder tumor cells resulted in overexpression of DBCCR1 and upregulation of SMPDL3A mRNA and protein. Only full-length DBCCR1 increased SMPDL3A expression, suggesting that the membrane attack complex/perforin domain of the N terminus of DBCCR1 is not sufficient for SMPDL3A interaction.
Kawano et al. (2004) showed that, like other BRINP family members, expression of fluorescence-tagged rat Brinp1 suppressed progression of NIH-3T3 cell cycle at the G1/S transition.
By flow cytometric analysis, Terashima et al. (2010) showed that expression of all 3 BRINP proteins suppressed cell-cycle progression of mouse NSCs.
Nishiyama et al. (1999) reported a case of superficial papillary transitional cell carcinoma of the bladder that showed a homozygous deletion encompassing the previously identified tumor suppressor region at chromosome 9q32-q33, which includes DBCCR1.
Izumi et al. (2005) identified a homozygous deletion of DBC1 in 2 of 53 primary nonsmall cell lung cancer (NSCLC) tumors and in 1 of 27 NSCLC cell lines. Moreover, 21 of the other 26 NSCLC cell lines showed complete loss of DBC1 expression, which is expressed in normal lung tissue, and treatment with 5-aza-2-prime-deoxycytidine restored its expression. A part of a CpG island around exon 1 of DBC1 showed promoter activity in vitro and was frequently methylated in the NSCLC cell lines and primary NSCLC tumors. Methylation status correlated inversely with gene expression. Exogenous overexpression of DBC1 in NSCLC cell lines lacking its expression inhibited cell growth. Izumi et al. (2005) proposed that DBC1 is a likely tumor suppressor for NSCLC and silencing of the gene through homozygous deletion or methylation of its promoter region may be associated with progression of this disease.
Berkowicz et al. (2016) noted that postnatal viability of pups from mothers carrying Brinp1 -/- alleles is compromised. Consequently, Berkowicz et al. (2016) found that Brinp2 -/- mice and Brinp3 -/- mice, as well as Brinp2 -/- Brinp3 -/- double-knockout mice, were viable and born at mendelian frequencies, whereas Brinp1 -/- Brinp2 -/- Brinp3 -/- triple-knockout mice exhibited poor viability. All 4 genotypes exhibited body mass reduction, but gross morphology was normal.
Berkowicz, S. R., Featherby, T. J., Whisstock, J. C., Bird, P. I. Mice lacking Brinp2 or Brinp3, or both, exhibit behaviors consistent with neurodevelopmental disorders. Front. Behav. Neurosci. 10: 196, 2016. [PubMed: 27826231] [Full Text: https://doi.org/10.3389/fnbeh.2016.00196]
Gross, M. B. Personal Communication. Baltimore, Md. 6/4/2021.
Habuchi, T., Luscombe, M., Elder, P. A., Knowles, M. A. Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32-q33. Genomics 48: 277-288, 1998. [PubMed: 9545632] [Full Text: https://doi.org/10.1006/geno.1997.5165]
Habuchi, T., Yoshida, O., Knowles, M. A. A novel candidate tumour suppressor locus at 9q32-33 in bladder cancer: localization of the candidate region within a single 840 kb YAC. Hum. Molec. Genet. 6: 913-919, 1997. [PubMed: 9175739] [Full Text: https://doi.org/10.1093/hmg/6.6.913]
Izumi, H., Inoue, J., Yokoi, S., Hosoda, H., Shibata, T., Sunamori, M., Hirohashi, S., Inazawa, J., Imoto, I. Frequent silencing of DBC1 is by genetic or epigenetic mechanisms in non-small cell lung cancers. Hum. Molec. Genet. 14: 997-1007, 2005. [PubMed: 15746151] [Full Text: https://doi.org/10.1093/hmg/ddi092]
Kawano, H., Nakatani, T., Mori, T., Ueno, S., Fukayama, M., Abe, A., Kobayashi, M., Toda, F., Watanabe, M., Matsuoka, I. Identification and characterization of novel developmentally regulated neural-specific proteins, BRINP family. Molec. Brain Res. 125: 60-75, 2004. [PubMed: 15193423] [Full Text: https://doi.org/10.1016/j.molbrainres.2004.04.001]
Nishiyama, H., Takahashi, T., Kakehi, Y., Habuchi, T., Knowles, M. A. Homozygous deletion at the 9q32-33 candidate tumor suppressor locus in primary human bladder cancer. Genes Chromosomes Cancer 26: 171-175, 1999. [PubMed: 10469456]
Terashima, M., Kobayashi, M., Motomiya, M., Inoue, N., Yoshida, T., Okano, H., Iwasaki, N., Minami, A., Matsuoka, I. Analysis of the expression and function of BRINP family genes during neuronal differentiation in mouse embryonic stem cell-derived neural stem cells. J. Neurosci. Res. 88: 1387-1393, 2010. [PubMed: 20025061] [Full Text: https://doi.org/10.1002/jnr.22315]
Wright, K. O., Messing, E. M., Reeder, J. E. Increased expression of the acid sphingomyelinase-like protein ASML3a in bladder tumors. J. Urol. 168: 2645-2649, 2002. [PubMed: 12442002] [Full Text: https://doi.org/10.1016/S0022-5347(05)64236-X]