Alternative titles; symbols
HGNC Approved Gene Symbol: P4HB
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:81,843,166-81,860,535 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Cole-Carpenter syndrome 1 | 112240 | Autosomal dominant | 3 |
The P4HB gene encodes protein disulfide isomerase (PDI), a ubiquitously expressed prototypical member of the disulfide isomerase family of proteins, which assist with the correct formation of disulfide bridges in nascent polypeptide chains and therefore are key enzymes for protein folding. PDI also participates in the posttranslational modification of procollagen type I (summary by Rauch et al., 2015).
Prolyl 4-hydroxylase (EC 1.14.11.2) is involved in hydroxylation of prolyl residues in preprocollagen. Pihlajaniemi et al. (1987) cloned the PROHB gene. Prolyl 4-hydroxylase is a tetramer consisting of 2 alpha (176710, 600608) and 2 beta subunits of molecular weights about 64,000 and 60,000, respectively, for the monomers. Characterization of cDNA clones for the human beta subunit indicated that the polypeptide is 508 amino acids long, including a signal peptide of 17 amino acids. Pihlajaniemi et al. (1987) also found that disulfide isomerase (EC 5.3.4.1) is a product of the same gene. When present in cells in monomeric form, the protein serves the function of DSI (Koivu et al., 1987); when present in the prolyl 4-hydroxylase tetramer, it catalyzes the formation of 4-hydroxyproline in collagen.
Cheng et al. (1987) demonstrated by molecular cloning and nucleotide sequencing that cellular thyroid hormone-binding protein is also identical to the beta subunit of prolyl 4-hydroxylase and protein disulfide isomerase.
The protein disulfide isomerase/oxidoreductase (EC 1.8.4.2) is the same enzyme molecule as P4HB (Noiva and Lennarz, 1992). Also known as glutathione-insulin transhydrogenase, it catalyzes thiol:protein-disulfide interchange. GSH-insulin transhydrogenase is a ubiquitous, abundant protein that is located primarily in endoplasmic reticulum (ER), but is also associated with plasma membrane and other intracellular membrane compartments. Morris and Varandani (1988) determined the nucleotide sequence of a cDNA isolated from a human liver cDNA expression library in lambda phage gt11 with monoclonal antibodies to rat liver protein disulfide isomerase/oxidoreductase. The largest cDNA contained approximately 1,500 basepairs and represented an estimated 65% of the message. They found 100% identity with rat enzyme in the active site region and 81% similarity in other regions.
Tasanen et al. (1988) isolated genomic clones for the human gene coding for this multifunctional protein. They found that the gene is about 18 kb long and consists of 11 exons. The codons for the 2 presumed active sites of protein disulfide isomerase, each a cys-gly-his-cys sequence, were found to be located 12 bp from the beginning of exons 2 and 9.
The P4HB gene was tentatively mapped to chromosome 7 by somatic cell hybridization (Pajunen et al., 1985). Pajunen et al. (1987, 1988) definitively assigned the gene for the beta subunit to chromosome 17, specifically, 17q23-q25. The identification in cell hybrids was performed by 3 different methods: immunoblotting using species-specific monoclonal antibodies, radioimmunoassay with species-specific polyclonal antibodies, and Southern blot analysis using cDNA for the human beta subunit.
The sequence of the cellular thyroid hormone-binding protein with a molecular weight of 55,000 (p55) indicates that it is identical to protein disulfide isomerase and the beta subunit of prolyl 4-hydroxylase. By in situ hybridization, using a cDNA for the human p55 gene, Popescu et al. (1988) localized the gene to 17q25. This indicated that the p55 gene is not linked to either of the 2 other thyroid hormone-binding protein genes, ERBA1 (190120) and ERBA2 (190160), which are located at 17q11-q21 and 3pter-p21, respectively.
Pajunen et al. (1991) confirmed the assignment of P4HB to 17q25 by in situ hybridization. Southern blot analysis of restricted DNA from a chromosome-mediated gene transfer transfectant panel suggested that the P4HB gene is located distal to the gene for thymidine kinase (TK1; 188300), either between the genes for thymidine kinase and galactokinase (GALK1; 604313) or on the telomeric side of both these genes.
Another of the many functions of protein disulfide isomerase is its role as the smaller element of the heterodimeric microsomal triglyceride transfer protein (MTP; 157147). The unique larger subunit of this heterodimer is mutant in patients with abetalipoproteinemia (200100). Since chylomicrons, very low density lipoproteins, and low density lipoproteins are absent from the plasma in abetalipoproteinemic subjects, and since the clinical pathology of abetalipoproteinemia results from deficiency of fat-soluble vitamins that are transported on apoB-containing lipoproteins, Sharp et al. (1993) proposed that inhibition of MTP may provide a specific mechanism for lowering plasma cholesterol and triglyceride levels.
Mezghrani et al. (2001) found that PDI functioned with the oxidoreductases ERO1L-alpha (ERO1L; 615435) and ERO1L-beta (ERO1LB; 615437) in disulfide bond formation. Overexpression of either ERO1L protein in HeLa cells accelerated oxidative folding of murine immunoglobulin J chain (IGJ; 147790). Immunoprecipitation analysis revealed that PDI, but not the ERO1L proteins, formed a mixed disulfide with IgJ during oxidative folding. PDI also formed mixed disulfides with ERO1L-alpha and ERO1L-beta. The ERO1L proteins oxidized PDI, but not the related oxidoreductase ERP57 (PDIA3; 602046). PDI was not oxidized by mutant ERO1L-alpha containing alanine substitutions of cys394 or cys397 within a critical CxxCxxC motif. Mezghrani et al. (2001) concluded that PDI transfers electrons from nascent cargo proteins to ERO1L recipients during oxidative protein folding.
PDI has 2 domains that function as independent active sites with homology to the small, redox-active protein thioredoxin (187700). During neurodegenerative disorders and cerebral ischemia, the accumulation of immature and denatured proteins results in ER dysfunction, but the upregulation of PDI represents an adaptive response to protect Uehara et al. (2006) demonstrated, in brains manifesting sporadic Parkinson (see 168601) or Alzheimer (see 104300) disease, that PDI is S-nitrosylated, a reaction NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. S-nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins, or proteasome inhibition. Thus, Uehara et al. (2006) concluded that PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.
Qi et al. (2008) reported physical interactions between Ago2 (606229) and the alpha (P4H-alpha-1) (P4HA1; 176710), and beta (P4H-beta, P4HB) subunits of the type I collagen prolyl-4-hydroxylase (C-P4H-I). Mass spectrometric analysis identified hydroxylation of the endogenous Ago2 at proline-700. In vitro, both Ago2 and Ago4 (607356) seem to be more efficiently hydroxylated than Ago1 (606228) and Ago3 (607355) by recombinant human C-P4H-I. Human cells depleted of P4H-alpha-1 or P4H-beta by short hairpin RNA, and C-P4H-alpha-I-null mouse embryonic fibroblast cells, showed reduced stability of Ago2 and impaired short interfering RNA-programmed RISC activity. Furthermore, mutation of proline-700 to alanine also resulted in destabilization of Ago2, thus linking Ago2 P700 and hydroxylation at this residue to its stability regulation. Qi et al. (2008) concluded that their findings identified hydroxylation as a posttranslational modification important for Ago2 stability and effective RNA interference.
Using human cell lines, Mueller et al. (2008) identified several components of a protein complex required for retrotranslocation or dislocation of misfolded proteins from the ER lumen to the cytosol for proteasome-dependent degradation. These included SEL1L (602329), HRD1 (SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97 (VCP; 601023), PDI, BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434), UBXD8 (FAF2), UBC6E (UBE2J1; 616175), and OS9 (609677).
Using mutation analysis, Wang et al. (2011) found that the cys-gly-his-gly active site in amino acids 352 to 462 of PDI was required for recombinant human PDI and ERO1L-beta to reactivate denatured and reduced RNase A (180440) in vitro.
By whole-exome sequencing in 2 unrelated male patients with Cole-Carpenter syndrome-1 (CLCRP1; 112240), who exhibited multiple fractures of the long bones as well as craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features, Rauch et al. (2015) identified heterozygosity for the same missense mutation in the P4HB gene (Y393C; 176790.0001) in both patients. The mutation occurred de novo in 1 patient; in the other family, the unaffected father was mosaic for the variant.
In 2 unrelated male patients with Cole-Carpenter syndrome-1 (CLCRP1; 112240), Rauch et al. (2015) identified heterozygosity for a c.1178A-G transition (c.1178A-G, NM_000918.3) in exon 9 of the P4HB gene, resulting in a tyr393-to-cys (Y393C) substitution at a highly conserved residue within the C-terminal disulfide isomerase domain. The mutation, which was not found in an in-house exome database or in the dbSNP, 1000 Genomes Project, NHLBI/NHGRI Exome Project, or Exome Aggregation Consortium databases, occurred de novo in 1 patient. In the other family, the unaffected father was mosaic for the variant, which was present in 23% of cells from saliva but was not detected in skin fibroblasts. Scrambled RNase A assay revealed impaired ability of the Y393C mutant to act as a disulfide isomerase compared to wildtype P4HB. Analysis of patient fibroblasts suggested that the Y393C mutant forms more stable disulfide bridges with substrate proteins than wildtype P4HB.
Cheng, S. Y., Gong, Q. H., Parkinson, C., Robinson, E. A., Appella, E., Merlino, G. T., Pastan, I. The nucleotide sequence of a human cellular thyroid hormone-binding protein present in endoplasmic reticulum. J. Biol. Chem. 262: 11221-11227, 1987. [PubMed: 3611107]
Koivu, J., Myllyla, R., Halaakoski, T., Pihlajaniemi, T., Tasanen, K., Kivirikko, K. I. A single polypeptide acts both as the beta subunit of prolyl 4-hydroxylase and as a protein disulfide-isomerase. J. Biol. Chem. 262: 6447-6449, 1987. [PubMed: 3032969]
Mezghrani, A., Fassio, A., Benham, A., Simmen, T., Braakman, I., Sitia, R. Manipulation of oxidative protein folding and PDI redox state in mammalian cells. EMBO J. 20: 6288-6296, 2001. [PubMed: 11707400] [Full Text: https://doi.org/10.1093/emboj/20.22.6288]
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Pajunen, L., Jones, T. A., Goddard, A., Sheer, D., Solomon, E., Pihlajaniemi, T., Kivirikko, K. I. Regional assignment of the human gene coding for a multifunctional polypeptide (P4HB) acting as the beta-subunit of prolyl 4-hydroxylase and the enzyme protein disulfide isomerase to 17q25. Cytogenet. Cell Genet. 56: 165-168, 1991. [PubMed: 1647289] [Full Text: https://doi.org/10.1159/000133078]
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Popescu, N. C., Cheng, S., Pastan, I. Chromosomal localization of the gene for a human thyroid hormone-binding protein. Am. J. Hum. Genet. 42: 560-564, 1988. [PubMed: 2831713]
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Rauch, F., Fahiminiya, S., Majewski, J., Carrot-Zhang, J., Boudko, S., Glorieux, F., Mort, J. S., Bachinger, H.-P., Moffatt, P. Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. Am. J. Hum. Genet. 96: 425-431, 2015. [PubMed: 25683117] [Full Text: https://doi.org/10.1016/j.ajhg.2014.12.027]
Sharp, D., Blinderman, L., Combs, K. A., Kienzle, B., Ricci, B., Wager-Smith, K., Gil, C. M., Turck, C. W., Bouma, M.-E., Rader, D. J., Aggerbeck, L. P., Gregg, R. E., Gordon, D. A., Wetterau, J. R. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 365: 65-69, 1993. [PubMed: 8361539] [Full Text: https://doi.org/10.1038/365065a0]
Tasanen, K., Parkkonen, T., Chow, L. T., Kivirikko, K. I., Pihlajaniemi, T. Characterization of the human gene for a polypeptide that acts both as the beta-subunit of prolyl 4-hydroxylase and as protein disulfide isomerase. J. Biol. Chem. 263: 16218-16224, 1988. [PubMed: 2846539]
Uehara, T., Nakamura, T., Yao, D., Shi, Z.-Q., Gu, Z., Ma, Y., Masliah, E., Nomura, Y., Lipton, S. A. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441: 513-517, 2006. [PubMed: 16724068] [Full Text: https://doi.org/10.1038/nature04782]
Wang, L., Zhu, L., Wang, C. The endoplasmic reticulum sulfhydryl oxidase Ero1-beta drives efficient oxidative protein folding with loose regulation. Biochem. J. 434: 113-121, 2011. [PubMed: 21091435] [Full Text: https://doi.org/10.1042/BJ20101357]