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HGNC Approved Gene Symbol: DNAJB1
Cytogenetic location: 19p13.12 Genomic coordinates (GRCh38) : 19:14,514,769-14,560,391 (from NCBI)
The E. coli heat-shock protein DnaJ functions together with DnaK (HSPA1A; 140550) and GrpE (GRPEL1; 606173) as a molecular chaperone, involving them in assembly and disassembly of protein complexes, protein folding, renaturation of denatured proteins, prevention of protein aggregation, and protein export. By screening a human placenta cDNA library with anti-Hsp40 antibody, Ohtsuka (1993) isolated a cDNA encoding a 40-kD heat-shock protein designated HSPF1. The deduced 340-amino acid HSPF1 protein is 34% identical to E. coli DnaJ and 34% and 36% identical to HSJ1 (604139) and HSJ2 (602837), respectively. By Northern blot analysis, Hata and Ohtsuka (1998) showed that expression of a major 2.4-kb and a minor 1.4-kb HSPF1 transcript is drastically induced by heat shock.
Hata et al. (1996) determined that the HSPF1 gene spans over 7 kb and contains 3 exons and 2 introns. The 5-prime region of the gene is highly GC rich, and there are multiple basal elements for transcription factors, including typical heat-shock elements (HSEs).
By FISH, Hata et al. (1996) mapped the HSPF1 gene to chromosome 19p13.2.
Hata and Ohtsuka (1998) found by gel mobility supershift assays that HSF1 (140580) but not HSF2 (140581) interacts with the 8 exonic HSEs of HSPF1. An intronic HSE in HSPF1 is inactive.
Several dominant human neurodegenerative diseases involve the expansion of a polyglutamine within the disease proteins. This expansion confers toxicity on the proteins and is associated with nuclear inclusion formation. Data indicate that molecular chaperones can modulate polyglutamine pathogenesis. To elucidate the basis of polyglutamine toxicity and the mechanism by which chaperones suppress neurodegeneration, Chan et al. (2000) studied transgenic Drosophila disease models of Machado-Joseph disease (109150) and Huntington disease (143100). They demonstrated that Hsp70 (see 140559) and Hdj1, the Drosophila homolog to human HSP40 (see 604139), showed substrate specificity for polyglutamine proteins as well as synergy in suppression of neurotoxicity, and altered the solubility properties of the mutant polyglutamine protein.
Using a Drosophila model for Huntington disease and other polyglutamine diseases to screen for genetic factors modifying the degeneration caused by expression of polyglutamine in the eye, Kazemi-Esfarjani and Benzer (2000) isolated several suppressor strains, 2 of which led to the discovery of suppressor genes. The predicted product of one is TPR2 (601964), which is homologous to the human tetratricopeptide repeat protein-2. That of the second is HDJ1. The suppression of polyglutamine toxicity was verified in transgenic flies.
Khan et al. (2016) analyzed HEK293 cells transfected with wildtype FOXE3 (601094) or an anterior segment dysgenesis (ASGD2; 610256)-associated FOXE3 mutant (C240X; 601094.0004) and found that only the DNAJB1 gene was differentially expressed in both transcriptome and proteome screens, showing downregulation with the C240X mutant compared to wildtype FOXE3. In mouse lenses, the authors detected expression of both Foxe3 and Dnajb1 as early as embryonic day 12.5, and observed a reciprocal expression pattern of the 2 genes in the developing mouse lens. Chromatin immunoprecipitation experiments confirmed that FOXE3 binds to the 5-prime UTR of DNAJB1 and modulates its transcriptional activity, and luciferase reporter constructs exhibited lower transcriptional activity for the putative FOXE3-binding site with the mutant compared to wildtype. In addition, overexpression of FOXE3 in HEK293 cells showed 3-fold higher expression of DNAJB1 in cells transfected with wildtype FOXE3 compared to cells expressing the C240X mutant. Knockdown of DNAJB1 in human lens epithelial cells resulted in mitotic arrest. Zebrafish with knockdown of a ubiquitously expressed DNAJB1 ortholog, dnajb1a, recapitulated the human phenotype, showing relatively smaller eyes with developmental defects, including an underdeveloped lens with total cataracts; there were also significantly increased apoptotic nuclei throughout the eye compared with control embryos. Knockdown of another DNAJB1 zebrafish ortholog that is expressed only in the lens, dnajb1b, resulted in mildly as well as severely affected morphants, with smaller eyes and protruding lenses compared to wildtype zebrafish, as well as total cataracts. Khan et al. (2016) concluded that DNAJB1 plays a crucial role in the development and maintenance of lens transparency.
Fibrolamellar hepatocellular carcinoma (see HCC, 114550) is a rare liver tumor affecting adolescents and young adults with no history of primary liver disease or cirrhosis. Honeyman et al. (2014) identified a chimeric transcript that is expressed in fibrolamellar HCC but not in adjacent normal liver and that arises as the result of an approximately 400-kb deletion on chromosome 19. The chimeric RNA is predicted to code for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in-frame with PRKACA (601639), the catalytic domain of protein kinase A. Immunoprecipitation and Western blot analyses confirmed that the chimeric protein is expressed in tumor tissue, and a cell culture assay indicated that it retains kinase activity. Evidence supporting the presence of the DNAJB1-PRKACA chimeric transcript in 100% of the fibrolamellar HCCs examined (15 of 15) suggests that this genetic alteration contributes to tumor pathogenesis.
Chan, H. Y. E., Warrick, J. M., Gray-Board, G. L., Paulson, H. L., Bonini, N. M. Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Molec. Genet. 9: 2811-2820, 2000. [PubMed: 11092757] [Full Text: https://doi.org/10.1093/hmg/9.19.2811]
Hata, M., Ohtsuka, K. Characterization of HSE sequences in human Hsp40 gene: structural and promoter analysis. Biochim. Biophys. Acta 1397: 43-55, 1998. [PubMed: 9545528] [Full Text: https://doi.org/10.1016/s0167-4781(97)00208-x]
Hata, M., Okumura, K., Seto, M., Ohtsuka, K. Genomic cloning of a human heat shock protein 40 (Hsp40) gene (HSPF1) and its chromosomal localization to 19p13.2. Genomics 38: 446-449, 1996. [PubMed: 8975727] [Full Text: https://doi.org/10.1006/geno.1996.0653]
Honeyman, J. N., Simon, E. P., Robine, N., Chiaroni-Clarke, R., Darcy, D. G., Lim, I. I. P., Gleason, C. E., Murphy, J. M., Rosenberg, B. R., Teegan, L., Takacs, C. N., Botero, S., Belote, R., Germer, S., Emde, A.-K., Vacic, V., Bhanot, U., LaQuaglia, M. P., Simon, S. M. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343: 1010-1014, 2014. [PubMed: 24578576] [Full Text: https://doi.org/10.1126/science.1249484]
Kazemi-Esfarjani, P., Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 287: 1837-1840, 2000. [PubMed: 10710314] [Full Text: https://doi.org/10.1126/science.287.5459.1837]
Khan, S. Y., Vasanth, S., Kabir, F., Gottsch, J. D., Khan, A. O., Chaerkady, R., Lee, M.-C. W., Leitch, C. C., Ma, Z., Laux, J., Villasmil, R., Khan, S. N., Riazuddin, S., Akram, J., Cole, R. N., Talbot, C. C., Pourmand, N., Zaghloul, N. A., Hejtmancik, J. F., Riazuddin, S. A. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nature Commun. 7: 10953, 2016. Note: Electronic Article. [PubMed: 27218149] [Full Text: https://doi.org/10.1038/ncomms10953]
Ohtsuka, K. Cloning of a cDNA for heat-shock protein Hsp40, a human homologue of bacterial DnaJ. Biochem. Biophys. Res. Commun. 197: 235-240, 1993. [PubMed: 8250930] [Full Text: https://doi.org/10.1006/bbrc.1993.2466]