Alternative titles; symbols
HGNC Approved Gene Symbol: PDIA6
Cytogenetic location: 2p25.1 Genomic coordinates (GRCh38): 2:10,783,391-10,837,712 (from NCBI)
Protein disulfide isomerases (EC 5.3.4.1), such as PDIA6, are endoplasmic reticulum (ER) resident proteins that catalyze formation, reduction, and isomerization of disulfide bonds in proteins and are thought to play a role in folding of disulfide-bonded proteins (Hayano and Kikuchi, 1995).
By screening a placenta cDNA library with a PDI (P4HB; 176790) cDNA fragment, Hayano and Kikuchi (1995) cloned PDIA6, which they called P5. The deduced 440-amino acid protein has a calculated molecular mass of 48.1 kD. It has a putative N-terminal signal sequence, followed by 2 thioredoxin (TXN; 187700)-like domains and a C-terminal ER retention signal (KDEL).
Chaudhuri et al. (1992) found that mouse P5 showed highest expression in lung, with progressively lower levels in kidney, heart, liver, and brain.
By in situ hybridization, Yang-Feng et al. (1987) mapped the PDIA6 gene to chromosome 2p25-p24.
Chaudhuri et al. (1992) showed that P5, Rrm2 (180410), and Odc1 (165640) were coamplified in hamster cells resistant to hydroxyurea, a potent inhibitor of ribonucleotide reductase. Since P5, RRM2, and ODC1 are closely linked in the hamster and human genomes, Chaudhuri et al. (1992) hypothesized that they may form an amplicon.
Kikuchi et al. (2002) found that recombinant human P5 had both isomerase and chaperone activities, but both activities were lower than those of human PDI. P5 showed peptide-binding activity, and its chaperone activity appeared to be substrate specific. Mutation analysis revealed that the first thioredoxin-like motif of P5 was more important than the second for isomerase activity, and that the first cysteine in each motif was necessary for isomerase activity. Thioredoxin motif mutants of P5 lacking isomerase activity retained chaperone activity with citrate synthase (CS; 118950) as substrate, indicating that, like PDI, the isomerase and chaperone activities of P5 are likely independent.
Kaiser et al. (2007) showed that on the surface of tumor cells, MICA (600169) associates with ERP5, which, similar to protein disulfide isomerase (176790), usually assists in the folding of nascent proteins inside cells. Pharmacologic inhibition of thioreductase activity and ERP5 gene silencing revealed that cell-surface ERP5 function is required for MICA shedding. ERP5 and membrane-anchored MICA formed transitory mixed disulfide complexes from which soluble MICA was released after proteolytic cleavage near the cell membrane. Kaiser et al. (2007) suggested that reduction of the seemingly inaccessible disulfide bond in the membrane-proximal alpha-3 domain of MICA must involve a large conformational change that enables proteolytic cleavage. They concluded that their results uncovered a molecular mechanism whereby domain-specific deconstruction regulates MICA protein shedding, thereby promoting tumor immune evasion, and identified surface ERP5 as a strategic target for therapeutic intervention.
The zebrafish 'one-eyed pinhead' (oep) mutation is characterized by multiple deficiencies in midline development and a morphologically normal notochord. Hoshijima et al. (2002) found that P5 was expressed predominantly in the axial mesoderm of midgastrula wildtype embryos and was significantly downregulated in oep mutants. Functional analysis demonstrated that P5 was specifically involved in lateral patterning. Depletion of P5 protein with antisense morpholino oligonucleotides revealed that P5 was required to establish asymmetric gene expression in the lateral plate mesoderm and brain and for regulating morphologic asymmetries in development of the heart, liver, and pancreas. Interference with P5 function did not perturb other aspects of midline development or function.
The mouse Pdia6 Akita mutation (C96Y) occurs at a position required for disulfide bond formation and results in mice with a diabetic phenotype. Gorasia et al. (2016) expressed FLAG-tagged proinsulin and mutant Akita proinsulin into a pancreatic beta cell line. In coimmunoprecipitation experiments, the Akita proinsulin pulled down about 10 times more Pdia6 protein than wildtype proinsulin. Gorasia et al. (2016) proposed that PDIA6 may act as a reductase to remove misfolded proinsulin through the ER-degradation pathway.
Choi et al. (2020) identified a recessive ENU-induced mutation in the first thioredoxin domain of Pdia6 (V32A, NP_082235.1; V27A, NP_082235.2) in mice with a syndromic phenotype of growth retardation, diabetes, and severe lymphoid and myeloid hypoplasia, which was designated 'braum.' Braum mice also had reduced T cell-independent antibody responses and premature death. Complete homozygous knockouts of Pdia6 were embryonic lethal.
Chhabra et al. (2021) generated mice with an F175S (NP_082235.1; F170S, NP_082235.2) mutation in the second thioredoxin domain of Pdia6, which resulted in the loss of pancreatic beta-cell identity at embryonic day (E) 18.5. The mice were mildly hyperglycemic at weaning and became hypoinsulinemic and diabetic as adults with the loss of beta-cell function but not the loss of cells as in typical type 1 diabetes. The studies of Choi et al. (2020) and Chhabra et al. (2021) implied that residues in PDIA6 at conserved positions in mice and humans play a critical role in beta-cell development and function.
For a discussion of a possible association between variation in the PDIA6 gene and short-rib thoracic dysplasia, see 611099.0001.
This variant is classified as a variant of unknown significance because its contribution to a form of short-rib thoracic dysplasia has not been confirmed.
In a Saudi male infant who died at age 10 months with short-rib thoracic dysplasia, neonatal-onset diabetes, and polycystic kidney disease, Al-Fadhli et al. (2021) identified homozygosity for a 1-bp deletion (c.703del, NM_001282704.1) in exon 8 of the PDIA6 gene, causing a frameshift predicted to result in a premature termination codon (Val235fs). His unaffected parents and healthy brother were heterozygous for the variant, which was not found in the Saudi Human Genome Project or gnomAD databases. RT-PCR of family blood samples demonstrated that RNA expression was reduced in a gene dosage-dependent manner based on the zygosity of the family members, consistent with a loss-of-function effect of the variant.
Al-Fadhli, F. M., Afqi, M., Sairafi, M. H., Almuntashri, M., Alharby, E., Alharbi, G., Abdud Samad, F., Hashmi, J. A., Zaytuni, D., Bahashwan, A. A., Choi, J. H., Peake, R. W. A., Beutler, B., Almontashiri, N. A. M. Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal-onset diabetes. Clin. Genet. 99: 694-703, 2021. [PubMed: 33495992] [Full Text: https://doi.org/10.1111/cge.13930]
Chaudhuri, M. M., Tonin, P. N., Lewis, W. H., Srinivasan, P. R. The gene for a novel protein, a member of the protein disulphide isomerase/Form I phosphoinositide-specific phospholipase C family, is amplified in hydroxyurea-resistant cells. Biochem. J. 281: 645-650, 1992. [PubMed: 1311171] [Full Text: https://doi.org/10.1042/bj2810645]
Chhabra, N. F., Amend, A.-L., Bastidas-Ponce, A., Sabrautzki, S., Tarquis-Medina, M., Sachs, S., Rubey, M., Lorenz-Depiereux, B., Feuchtinger, A., Bakhti, M., Lickert, H., Przemeck, G. K. H., de Angelis, M. H. A point mutation in the Pdia6 gene results in loss of pancreatic beta-cell identity causing overt diabetes. Molec. Metab. 54: 101334, 2021. [PubMed: 34487921] [Full Text: https://doi.org/10.1016/j.molmet.2021.101334]
Choi, J. H., Zhong, X., Zhang, Z., Su, L., McAlpine, W., Misawa, T., Liao, T.-C., Zhan, X., Russell, J., Ludwig, S., Li, X., Tang, M., Anderton, P., Moresco, E. M. Y., Beutler, B. Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development. J. Exp. Med. 217: e20190006, 2020. [PubMed: 31985756] [Full Text: https://doi.org/10.1084/jem.20190006]
Gorasia, D. G., Dudek, N. L., Safavi-Hemami, H., Perez, R. A., Schittenhelm, R. B., Saunders, P. M., Wee, S., Mangum, J. E., Hubbard, M. J., Purcell, A. W. A prominent role of PDIA6 in processing of misfolded proinsulin. Biochim. Biophys. Acta 1864: 715-723, 2016. [PubMed: 26947243] [Full Text: https://doi.org/10.1016/j.bbapap.2016.03.002]
Hayano, T., Kikuchi, M. Cloning and sequencing of the cDNA encoding human P5. Gene 164: 377-378, 1995. [PubMed: 7590364] [Full Text: https://doi.org/10.1016/0378-1119(95)00474-k]
Hoshijima, K., Metherall, J. E., Grunwald, D. J. A protein disulfide isomerase expressed in the embryonic midline is required for left/right asymmetries. Genes Dev. 16: 2518-2529, 2002. [PubMed: 12368263] [Full Text: https://doi.org/10.1101/gad.1001302]
Kaiser, B. K., Yim, D., Chow, I.-T., Gonzalez, S., Dai, Z., Mann, H. H., Strong, R. K., Groh, V., Spies, T. Disulphide-isomerase-enabled structure of tumour-associated NKG2D ligands. Nature 447: 482-486, 2007. [PubMed: 17495932] [Full Text: https://doi.org/10.1038/nature05768]
Kikuchi, M., Doi, E., Tsujimoto, I., Horibe, T., Tsujimoto, Y. Functional analysis of human P5, a protein disulfide isomerase homologue. J. Biochem. 132: 451-455, 2002. [PubMed: 12204115] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a003242]
Yang-Feng, T. L., Barton, D. E., Thelander, L., Lewis, W. H., Srinivasan, P. R., Francke, U. Ribonucleotide reductase M2 subunit sequences mapped to four different chromosomal sites in humans and mice: functional locus identified by its amplification in hydroxyurea-resistant cell lines. Genomics 1: 77-86, 1987. [PubMed: 3311968] [Full Text: https://doi.org/10.1016/0888-7543(87)90108-x]