Alternative titles; symbols
HGNC Approved Gene Symbol: DNAJB11
Cytogenetic location: 3q27.3 Genomic coordinates (GRCh38): 3:186,570,720-186,585,793 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q27.3 | Polycystic kidney disease 6 with or without polycystic liver disease | 618061 | Autosomal dominant | 3 |
The DNAJB11 gene encodes a soluble glycoprotein of the endoplasmic reticulum (ER) that acts as a cofactor of GRP78 (HSPA5; 138120), a heat shock protein chaperone required for the proper folding, assembly, trafficking, and degradation of proteins. DNAJB11 thus plays a role in ER protein homeostasis (summary by Cornec-Le Gall et al., 2018).
DNAJB11 belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus; a glycine/phenylalanine (G/F)-rich region; and a C-terminal cysteine-rich region (Ohtsuka and Hata, 2000).
By searching EST databases for J domain-containing proteins, Ohtsuka and Hata (2000) identified 10 mouse and human DNAJ homologs, including mouse Dnajb11. The deduced type II transmembrane protein contains 358 amino acids with an N-terminal J domain. Dnajb11 is predicted to have an N-terminal signal peptide.
Using database analysis to identify human homologs of a protein involved in Shiga toxin trafficking in monkey kidney cells, followed by PCR of a human skeletal muscle cDNA library, Yu et al. (2000) cloned DNAJB11, which they called HEDJ. Northern blot analysis detected transcripts of 2.2 and 2.0 kb in all tissues examined, with highest expression in pancreas and testis, and weakest expression in thymus and small intestine. Confocal microscopy showed that epitope-tagged DNAJB11 localized to the endoplasmic reticulum (ER). Protease susceptibility, glycosidase treatment, and detergent solubility assays demonstrated that DNAJB11 is luminally oriented and membrane-associated.
Using APOBEC1 (600130) as bait in a yeast 2-hybrid analysis of a liver cDNA library, followed by 5-prime RACE, Lau et al. (2001) cloned DNAJB11, which they called ABBP2. The deduced 358-amino acid protein has a calculated molecular mass of 40.5 kD and shares 99% sequence identity with the mouse protein. DNAJB11 contains a conserved J domain, a weak G/F region, and a region that contains 4 cysteines but lacks the zinc finger domain found in some DNAJ proteins. The secondary and tertiary structures of DNAJB11 closely resemble those of HDJ1 (DNAJB1; 604570). Northern blot analysis detected transcripts of 1.5 and 2.0 kb in all tissues examined.
Gross (2021) mapped the DNAJB11 gene to chromosome 3q27.3 based on an alignment of the DNAJB11 sequence (GenBank BC001144) with the genomic sequence (GRCh38).
Using in vitro experiments, Yu et al. (2000) demonstrated that the J domain of DNAJB11 interacted with the ER-associated heat-shock protein BIP (HSPA5; 138120) in an ATP-dependent manner and was capable of stimulating its ATPase activity.
Lau et al. (2001) showed that DNAJB11 bound to APOBEC1 via its J domain and neighboring G/F domain. Downregulation of DNAJB11 expression in a human hepatocarcinoma cell line inhibited endogenous APOBEC1-mediated apolipoprotein B (APOB; 107730) mRNA editing. Like other HSP40 proteins, DNAJB11 bound to HSP70 (see HSPA1A, 140550) and had ATPase-stimulating activity. APOBEC1-mediated APOB mRNA editing activity of in vitro tissue extracts required the presence of HSP70/DNAJB11. Although exogenously added ATP was not required for editing activity, removal of the endogenous ATP present in these extracts disrupted DNAJB11-HSP70 interaction and completely inhibited editing.
In affected members of 7 unrelated multigenerational families with autosomal dominant polycystic kidney disease-6 with or without polycystic liver disease (PKD6; 618061), Cornec-Le Gall et al. (2018) identified 5 different heterozygous mutations in the DNAJB11 gene (611341.0001-611341.0005). Mutations in the first 2 families were found by whole-exome sequencing through large screening studies, whereas the remaining mutations were found by targeted next-generation sequencing of candidate genes among 591 families. All mutations were confirmed by Sanger sequencing and segregated with the disorder in the families. The mutations included 2 missense, 2 frameshift, and 1 nonsense, all of which occurred in the J domain, through which DNAJB11 interacts with BIP (HSPA5; 138120), or in the substrate-binding domain. Functional studies of the variants were not performed. Analysis of DNAJB11-null human renal cortical tubular epithelial cells showed decreased levels of mature cleaved polycystin-1 (PKD1; 601313) and increased levels of full-length immature PKD1, indicating a defect in the maturation process. Membrane expression of PKD1 was also significantly decreased in DNAJB11-null cells, consistent with a trafficking defect. There was no evidence of activation of the unfolded protein response in these cells. Kidney tissue samples from 2 unrelated patients showed some abnormal intracellular retention of uromodulin (UMOD; 191845) and MUC1 (158340) in epithelial cells in the thick ascending loop of Henle, suggesting that tubulointerstitial kidney disease may be a component of the disorder (see ADTKD1, 162000).
In affected members of a multigenerational family (family 1) with autosomal dominant polycystic kidney disease-6 with or without polycystic liver disease (PKD6; 618061), Cornec-Le Gall et al. (2018) identified a heterozygous c.161C-G transversion (c.161C-G, NM_016306.5) in exon 2 of the DNAJB11 gene, resulting in a pro54-to-arg (P54R) substitution at a highly conserved residue in the HPD motif of the J domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Functional studies of the variant were not performed.
In affected members of a multigenerational family (family 2) with autosomal dominant polycystic kidney disease-6 with or without polycystic liver disease (PKD6; 618061), Cornec-Le Gall et al. (2018) identified a heterozygous 2-bp insertion (c.166_167insTT, NM_016306.5) in the DNAJB11 gene, resulting in a frameshift and premature termination (Arg56LeufsTer40) within the J domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In affected members of a multigenerational family (family 3) with autosomal dominant polycystic kidney disease-6 with or without polycystic liver disease (PKD6; 618061), Cornec-Le Gall et al. (2018) identified a heterozygous 1-bp deletion (c.479delC, NM_016306.5) in exon 6 of the DNAJB11 gene, resulting in a frameshift and premature termination (Ala160GlufsTer27) within the substrate-binding domain. The mutation, which was found by targeted next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In affected members of a multigenerational family (family 4) with autosomal dominant polycystic kidney disease-6 without polycystic liver disease (PKD6; 618061), Cornec-Le Gall et al. (2018) identified a heterozygous c.230T-C transition (c.230T-C, NM_016306.5) in exon 4 of the DNAJB11 gene, resulting in a leu77-to-pro (L77P) substitution at a highly conserved residue in the J domain. The mutation, which was found by targeted next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In affected members of 3 unrelated multigenerational families (families 5, 6, and 7) with autosomal dominant polycystic kidney disease-6 with or without polycystic liver disease (PKD6; 618061), Cornec-Le Gall et al. (2018) identified a heterozygous c.616C-T transition (c.616C-T, NM_016306.5) in exon 7 of the DNAJB11 gene, resulting in an arg206-to-ter (R206X) substitution within the substrate-binding domain. The mutation, which was found by targeted next-generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant were not performed.
Cornec-Le Gall, E., Olson, R. J., Besse, W., Heyer, C. M., Gainullin, V. G., Smith, J. M., Audrezet, M.-P., Hopp, K., Porath, B., Shi, B., Baheti, S., Senum, S. R., and 18 others. Monoallelic mutations to DNAJB11 cause atypical autosomal-dominant polycystic kidney disease. Am. J. Hum. Genet. 102: 832-844, 2018. [PubMed: 29706351] [Full Text: https://doi.org/10.1016/j.ajhg.2018.03.013]
Gross, M. B. Personal Communication. Baltimore, Md. 2/12/2021.
Lau, P. P., Villanueva, H., Kobayashi, K., Nakamuta, M., Chang, B. H.-J., Chan, L. A DnaJ protein, Apobec-1-binding protein-2, modulates apolipoprotein B mRNA editing. J. Biol. Chem. 276: 46445-46452, 2001. [PubMed: 11584023] [Full Text: https://doi.org/10.1074/jbc.M109215200]
Ohtsuka, K., Hata, M. Mammalian HSP40/DNAJ homologs: cloning of novel cDNAs and a proposal for their classification and nomenclature. Cell Stress Chaperones 5: 98-112, 2000. [PubMed: 11147971] [Full Text: https://doi.org/10.1379/1466-1268(2000)005<0098:mhdhco>2.0.co;2]
Yu, M., Haslam, R. H. A., Haslam, D. B. HEDJ, an Hsp40 co-chaperone localized to the endoplasmic reticulum of human cells. J. Biol. Chem. 275: 24984-24992, 2000. [PubMed: 10827079] [Full Text: https://doi.org/10.1074/jbc.M000739200]