Alternative titles; symbols
HGNC Approved Gene Symbol: DNAJC21
Cytogenetic location: 5p13.2 Genomic coordinates (GRCh38): 5:34,929,559-34,958,964 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.2 | Bone marrow failure syndrome 3 | 617052 | Autosomal recessive | 3 |
DNAJC21 belongs to a highly conserved family of proteins that are involved in protein translation, folding, unfolding, translocation, and degradation, primarily by stimulating the ATPase activity of members of the HSP70 (see HSPA1A, 140550) family of chaperone proteins (summary by Qiu et al., 2006).
During a large-scale sequence analysis of a human fetal brain cDNA library, Chen et al. (2004) cloned DNAJC21, which they called DNAJA5. The deduced 531-amino acid protein has a calculated molecular mass of 62.1 kD. It has an N-terminal J-domain with an absolutely conserved HPD tripeptide, followed by several GF residues and 2 C2H2-type zinc fingers, one in the central region and the other in the C terminus. The human protein shares 38.8% and 33.2% identity with rat and C. elegans orthologs, respectively. RT-PCR detected DNAJA5 in human brain, placenta, kidney, and pancreas, but not in heart, lung, liver, or skeletal muscle. By database analysis, Tummala et al. (2016) found that DNAJC21 was ubiquitously expressed in human tissues. Immunohistochemical analysis detected DNAJC21 in both the cytoplasm and the nucleus of HeLa and 293T cells. Within the nucleus, it localized primarily to the nucleolus.
Tummala et al. (2016) found that DNAJC21 translocated from the cytoplasm to the nucleus following inhibition of rRNA synthesis. Immunoprecipitation analysis of nuclear extracts of transfected HeLa cells revealed that fluorescence-tagged DNAJC21 interacted with the precursor 45S rRNA (see RNR1 180450) and with the 60S ribosome maturation factors PA2G4 (602145), ZNF622 (608694), and HSPA8 (600816). Knockdown of DNAJC21 in HeLa cells via small interfering RNA caused cytoplasmic accumulation of PA2G4, elongated cell morphology, and cell death. Reintroduction of DNAJC21 rescued cell viability and restored normal PA2G4 trafficking. Tummala et al. (2016) concluded that DNAJC21 is involved in nucleolar rRNA biogenesis and in cytoplasmic recycling of nuclear export factor PA2G4 for 60S ribosomal subunit maturation.
Chen et al. (2004) determined that the DNAJC21 gene has at least 12 exons and spans more than 25.6 kb.
By genomic sequence analysis, Chen et al. (2004) mapped the DNAJC21 gene to chromosome 5p13-p12.
Hartz (2016) mapped the DNAJC21 gene to chromosome 5p13.2 based on an alignment of the DNAJC21 sequence (GenBank AK022694) with the genomic sequence (GRCh38).
In 4 unrelated children, all born of consanguineous parents, with bone marrow failure syndrome-3 (BMFS3; 617052), Tummala et al. (2016) identified homozygous mutations in the DNAJC21 gene (617048.0001-617048.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Three of the mutations were predicted to result in a truncated protein with a loss of function; the fourth was a missense mutation. In vitro functional expression studies of 1 of the truncating mutations (R173X; 617048.0001) showed that it did not interact with 60S ribosome maturation factors, consistent with a loss of function. Studies of the missense mutation (P32A; 617048.0003) showed that it failed to interact with HSPA8 (600816). T cells from 1 patient with a truncating mutation (617048.0004) showed a growth impairment after mitogenic stimulation, decreased cell viability in response to actinomycin D, and decreased levels of rRNA subunits compared to controls. The findings suggested that the mutations resulted in defects in ribosome biogenesis.
In 4 patients from 3 unrelated families with BMFS3, Dhanraj et al. (2017) identified homozygous mutations in the DNAJC21 gene, including a nonsense (Q174X; 617048.0005) and a missense (K34E; 617048.0006) mutation and an intragenic deletion. The mutations, which were found by a combination of whole-exome sequencing and homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient cells showed decreased levels of DNAJC21 protein, consistent with a loss of function. Additional functional studies of the variants were not performed.
D'Amours et al. (2018) identified homozygosity for the K34E mutation in 5 unrelated patients with BMFS3. Functional studies of the variant were not performed.
In a French girl, born of consanguineous parents, with bone marrow failure syndrome-3 (BMFS3; 617052), Tummala et al. (2016) identified a homozygous c.517C-T transition (c.517C-T, NM_001012339.2) in the DNAJC21 gene, resulting in an arg173-to-ter (R173X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database. In vitro functional expression studies showed that the R173X mutant failed to interact with DNAJC21 partners, consistent with a loss of function. Moreover, the mutant transcript was predicted to result in nonsense-mediated mRNA decay in vivo.
In a girl, born of consanguineous parents of Algerian descent, with bone marrow failure syndrome-3 (BMFS3; 617052), Tummala et al. (2016) identified a homozygous c.983+1G-T transversion (c.983+1G-T, NM_001012339.2) in the DNAJC21 gene, resulting in a splice site defect, the skipping of exon 7, a frameshift, and premature termination (Gly299AlafsTer2). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was found at a low frequency (5 of 120,170 alleles) in the heterozygous state in the ExAC database.
In a boy, born of consanguineous parents of Pakistani descent, with bone marrow failure syndrome-3 (BMFS3; 617052), Tummala et al. (2016) identified a homozygous c.94C-G transversion (c.94C-G, NM_001012339.2) in the DNAJC21 gene, resulting in a pro32-to-ala (P32A) substitution at a highly conserved residue in the HPD motif that lies at the heart of the J domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database. The mutation was predicted to disrupt protein interactions, and in vitro studies showed that it failed to interact with HSPA8 (600816).
In a girl, born of consanguineous parents of Pakistani descent, with bone marrow failure syndrome-3 (BMFS3; 617052), Tummala et al. (2016) identified a homozygous c.793G-T transversion (c.793G-T, NM_001012339.2) in the DNAJC21 gene, resulting in a glu265-to-ter (E265X) substitution in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database. Patient-derived T cells showed a lack of DNAJC21 immunoreactivity, growth impairment after mitogenic stimulation, decreased cell viability in response to actinomycin D, and decreased levels of rRNA subunits compared to controls. All of these findings were consistent with a loss of function and a defect in ribosome biogenesis.
In a girl, born of consanguineous Afghan parents (family 1), with bone marrow failure syndrome-3 (BMFS3; 617052), Dhanraj et al. (2017) identified a homozygous c.520C-T transition (c.520C-T, NM_001012339.2) in exon 5 of the DNAJC21 gene, resulting in a gln174-to-ter (Q174X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed markedly reduced DNAJC21 protein levels compared to controls.
In 2 sibs, born of consanguineous parents of First Nations Canadian ancestry (family 2), with bone marrow failure syndrome-3 (BMFS3; 617052), Dhanraj et al. (2017) identified a homozygous c.100A-G transition in exon 2 of the DNAJC21 gene, resulting in a lys34-to-glu (K34E) substitution at a highly conserved residue in the J domain. The mutation, which was found by a combination of homozygosity mapping and direct Sanger sequencing, segregated with the disorder in the family. Patient cells showed about a 40% reduction in DNAJC21 protein levels compared to controls.
D'Amours et al. (2018) identified a homozygous K34E mutation in 5 unrelated patients with BMFS3. Functional studies of the variant were not performed.
Chen, J., Yin, G., Lu, Y., Lou, M., Cheng, H., Ni, X., Hu, G., Luo, C., Ying, K., Xie, Y., Mao, Y. Cloning and characterization of a novel human cDNA encoding a J-domain protein (DNAJA5) from the fetal brain. Int. J. Molec. Med. 13: 735-740, 2004. [PubMed: 15067379]
D'Amours, G., Lopes, F., Gauthier, J., Saillour, V., Nassif, C., Wynn, R., Alos, N., Leblanc, T., Capri, Y., Nizard, S., Lemyre, E., Michaud, J. L., Pelletier, V.-A., Pastore, Y. D., Soucy, J.-F. Refining the phenotype associated with biallelic DNAJC21 mutations. Clin. Genet. 94: 252-258, 2018. [PubMed: 29700810] [Full Text: https://doi.org/10.1111/cge.13370]
Dhanraj, S., Matveev, A., Li, H., Lauhasurayotin, S., Jardine, L., Cada, M., Zlateska, B., Tailor, C. S., Zhou, J., Mendoza-Londono, R., vincent, A., Durie, P. R., Scherer, S. W., Rommens, J. M., Heon, E., Dror, Y. Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome. (Letter) Blood 129: 1557-1562, 2017. [PubMed: 28062395] [Full Text: https://doi.org/10.1182/blood-2016-08-735431]
Hartz, P. A. Personal Communication. Baltimore, Md. July 21, 2016.
Qiu, X.-B., Shao, Y.-M., Miao, S., Wang, L. The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cell. Molec. Life Sci. 63: 2560-2570, 2006. [PubMed: 16952052] [Full Text: https://doi.org/10.1007/s00018-006-6192-6]
Tummala, H., Walne, A. J., Williams, M., Bockett, N., Collopy, L., Cardoso, S., Ellison, A., Wynn, R., Leblanc, T., Fitzgibbon, J., Kelsell, D. P., van Heel, D. A., Payne, E., Plagnol, V., Dokal, I., Vulliamy, T. DNAJC21 mutations link a cancer-prone bone marrow failure syndrome to corruption in 60S ribosome subunit maturation. Am. J. Hum. Genet. 99: 115-124, 2016. [PubMed: 27346687] [Full Text: https://doi.org/10.1016/j.ajhg.2016.05.002]