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HGNC Approved Gene Symbol: PRKCSH
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:11,435,635-11,450,968 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Polycystic liver disease 1 | 174050 | Autosomal dominant | 3 |
The PRKCSH gene encodes the noncatalytic beta subunit of glucosidase II. Glucosidase II activity (see 104160) is necessary for proper folding and quality control of proteins passing through the endoplasmic reticulum (ER) translocon (see 609213). The glucosidase II beta subunit encoded by PRKCSH contains an ER luminal retention signal and is required for glucosidase II function (summary by Fedeles et al., 2011).
Acidic proteins with an approximate molecular mass of 80 kD are prominent substrates for Ca(2+)/phospholipid-dependent protein kinase (protein kinase C; 176960, 176970, 176980). On the basis of the previous finding that human squamous carcinoma cells contain 2 distinct species of the 80-kD protein, 80K-H and 80K-L (177061), Minoshima et al. (1989) and Sakai et al. (1989) purified the 80K-H protein, determined a partial amino acid sequence, and synthesized a corresponding DNA probe. The PRKCSH cDNA encodes a protein of 527 amino acids. The deduced amino acid sequence showed a highly glutamic acid-rich region.
Trombetta et al. (1996) isolated enzymatically active glucosidase II from rat liver and found that it was composed of 2 subunits, alpha (104160) and beta. Based on peptide sequences of the purified enzyme, they identified the corresponding human cDNAs in existing sequence databases. Trombetta et al. (1996) reported that the available sequence of the beta subunit of human glucosidase II predicts a 514-amino acid protein with a putative endoplasmic reticulum retention signal.
Drenth et al. (2003) referred to the protein product of the PRKCSH gene as hepatocystin and predicted it to be localized to the endoplasmic reticulum.
Drenth et al. (2003) stated that the PRKCSH gene consists of 18 exons in a 15-kb interval.
Using a DNA probe corresponding to the 80K-H protein, Sakai et al. (1989) mapped the PRKCSH gene to chromosome 19 by spot blot hybridization to flow-sorted human chromosomes. The PRKCSH gene lies within the critical region on 19p13.2-p13.1 established for autosomal dominant polycystic liver disease (174050) (Reynolds et al., 2000; Li et al., 2003).
Polycystic liver disease-1 with or without kidney cysts (PCLD1; 174050) is a dominantly inherited condition characterized by the presence of multiple liver cysts of biliary epithelial origin. Although the clinical presentation and histologic features of polycystic liver disease in the presence or absence of autosomal dominant polycystic kidney disease are indistinguishable, a genetically distinct form of isolated polycystic liver disease is supported by the finding of linkage to 19p (Reynolds et al., 2000), a site distinct from those of the 2 forms of autosomal dominant polycystic kidney disease, PKD1 (173900) and PKD2 (613095).
By studying the same 2 large kindreds with PCLD1 investigated by Reynolds et al. (2000) and an additional family, Li et al. (2003) defined flanking markers in a region of approximately 3 Mb containing more than 70 candidate genes. Using a combination of denaturing high-performance liquid chromatography (DHPLC) heteroduplex analysis and direct sequencing, they screened a panel of 15 unrelated affected individuals for mutations in genes from this interval. They found sequence variations in the PRKCSH gene that were not observed in control individuals, that segregated with the disease haplotype, and that were predicted to be chain-terminating mutations. In light of the focal nature of liver cysts in autosomal dominant polycystic liver disease, the apparent loss-of-function mutations in PRKCSH, and the 2-hit mechanism operational in dominant polycystic kidney disease, they suggested that this disorder may also occur by a 2-hit mechanism.
Drenth et al. (2003) narrowed the critical region for PCLD on 19p to a 2.1-cM interval containing 78 genes and EST clusters. After sequencing 677 exons representing 94% of those in the genetic region of question, they detected a heterozygous mutation, 1138-2A-G (177060.0001), at the splice acceptor site of exon 16 of the PRKCSH gene. This mutation segregated in all affected members of 3 families. A second heterozygous change, at the splice donor site of intron 4 (177060.0002), segregated with all affected individuals in a fourth family.
Gao et al. (2010) showed that overexpression or depletion of Prkcsh in zebrafish embryos led to pronephric cysts, abnormal body curvature, and situs inversus. Identical phenotypic changes were induced by depletion or overexpression of Pkd2 (173910). Increased Prkcsh levels ameliorated developmental abnormalities caused by overexpressed Pkd2, whereas excess Pkd2 could compensate the loss of Prkcsh, indicating that the proteins may share a common signaling pathway. Prkcsh bound the C-terminal domain of Pkd2, and both proteins colocalized within the ER. Furthermore, Prkcsh interacted with Herp (HERPUD1; 608070) and inhibited Herp-mediated ubiquitination of Pkd2. Gao et al. (2010) suggested that PRKCSH may function as a chaperone-like molecule, which may prevent ER-associated degradation (ERAD) of Pkd2. Disequilibrium between PKD2 and PRKCSH may lead to cyst formation in PCLD patients with PRKCSH mutations, and thereby account for the overlapping manifestations observed in PCLD and autosomal dominant polycystic kidney disease.
Mutations in PRKCSH or SEC63 (608648) cause autosomal dominant polycystic liver disease. Fedeles et al. (2011) found that homozygous deletion of either Prkcsh or Sec63 in mice led to early embryonic lethality. Kidney- or liver-specific inactivation of either gene resulted in polycystic kidney or liver disease, respectively. Knockout of both genes increased the severity of cyst formation. Using a combination of targeted knockout and overexpression with these 2 genes and 3 other major genes mutated in polycystic kidney disease, Pkd1 (601313), Pkd2, and Pkhd1 (606702), Fedeles et al. (2011) produced a spectrum of cystic disease severity. Cyst formation in all combinations of these genes, except complete loss of Pkd2, was significantly modulated by altering expression of Pkd1. Proteasome inhibition increased the steady-state levels of Pkd1 in cells lacking Prkcsh and reduced cystic disease in mouse models of autosomal dominant polycystic liver disease. Fedeles et al. (2011) concluded that PRKCSH, SEC63, PKD1, PKD2, and PKHD1 form an interaction network with PKD1 as the rate-limiting component.
In 3 Dutch families, Drenth et al. (2003) found that members affected by autosomal dominant polycystic liver disease-1 without kidney cysts (PCLD1; 174050) were heterozygous for a mutation of adenine to guanine (1138-2A-G) at the splice acceptor site of exon 16 of the PRKCSH gene.
In all affected members of a family with autosomal dominant polycystic liver disease-1 without kidney cysts (PCLD1; 174050), Drenth et al. (2003) found a heterozygous change from guanine to cytosine (292+1G-C) in the splice donor site of intron 4 of the PRKCSH gene.
In family 1 with autosomal dominant polycystic liver disease without kidney cysts (PCLD1; 174050) in which linkage study was performed by Reynolds et al. (2000), Li et al. (2003) demonstrated a deletion of 2 bp at the 5-prime splice site of intron 16 in the PRKCSH gene. This resulted in skipping of exon 16 in a transcript in which exon 15 was spliced to exon 17, causing a frameshift and premature termination.
In family 2 with autosomal dominant polycystic liver disease without kidney cysts (PCLD1; 174050) in which Reynolds et al. (2000) demonstrated linkage between PCLD and 19p, Li et al. (2003) found a 1237C-T transition in exon 14 of the PRKCSH gene, resulting in a premature termination codon, gln413 to stop (Q413X). This mutation segregated with the affected haplotype.
In a family in which 3 members had autosomal dominant polycystic liver disease-1 without kidney cysts (PCLD1; 174050), Li et al. (2003) found a 1266C-G transversion in exon 15 of the PRKCSH gene resulting in a nonsense mutation, tyr422 to stop (Y422X).
In 2 affected members of a family with autosomal dominant polycystic liver disease-1 without kidney cysts (PCLD1; 174050), Li et al. (2003) found a 1-bp insertion (216insA) in exon 4 of the PRKSCH gene resulting in a frameshift and premature termination at amino acid residue 84 (Asn72fsTer84).
In a 49-year-old man with autosomal dominant polycystic liver disease-1 with kidney cysts (PCLD1; 174050), Cornec-Le Gall et al. (2018) identified a heterozygous c.1386T-G transversion in the PRKCSH gene, resulting in a tyr462-to-ter (Y462X) substitution. The patient had predominant polycystic liver disease requiring liver resection, and 8 cysts in the left kidney. A right nephrectomy was performed for atrophic cystic kidney with suspected malignancy. Functional studies of the variant and studies of patient cells were not performed.
Cornec-Le Gall, E., Torres, V. E., Harris, P. C. Genetic complexity of autosomal dominant polycystic kidney and liver diseases. J. Am. Soc. Nephrol. 29: 13-23, 2018. [PubMed: 29038287] [Full Text: https://doi.org/10.1681/ASN.2017050483]
Drenth, J. P. H., te Morsche, R. H. M., Smink, R., Bonifacino, J. S., Jansen, J. B. M. J. Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nature Genet. 33: 345-348, 2003. [PubMed: 12577059] [Full Text: https://doi.org/10.1038/ng1104]
Fedeles, S. V., Tian, X., Gallagher, A.-R., Mitobe, M., Nishio, S., Lee, S. H., Cai, Y., Geng, L., Crews, C. M., Somlo, S. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nature Genet. 43: 639-647, 2011. [PubMed: 21685914] [Full Text: https://doi.org/10.1038/ng.860]
Gao, H., Wang, Y., Wegierski, T., Skouloudaki, K., Putz, M., Fu, X., Engel, C., Boehlke, C., Peng, H., Kuehn, E. W., Kim, E., Kramer-Zucker, A., Walz, G. PRKCSH/80K-H, the protein mutated in polycystic liver disease, protects polycystin-2/TRPP2 against HERP-mediated degradation. Hum. Molec. Genet. 19: 16-24, 2010. [PubMed: 19801576] [Full Text: https://doi.org/10.1093/hmg/ddp463]
Li, A., Davila, S., Furu, L., Qian, Q., Tian, X., Kamath, P. S., King, B. F., Torres, V. E., Somlo, S. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am. J. Hum. Genet. 72: 691-703, 2003. [PubMed: 12529853] [Full Text: https://doi.org/10.1086/368295]
Minoshima, S., Hirai, M., Sakai, K., Kudoh, J., Fukuyama, R., Maekawa, M., Shimizu, N. Assignment of the gene for a protein kinase C substrate, 80K protein, to human chromosome 19. (Abstract) Cytogenet. Cell Genet. 51: 1045 only, 1989.
Reynolds, D. M., Falk, C. T., Li, A., King, B. F., Kamath, P. S., Huston, J., III, Shub, C., Iglesias, D. M., Martin, R. S., Pirson, Y., Torres, V. E., Somlo, S. Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am. J. Hum. Genet. 67: 1598-1604, 2000. [PubMed: 11047756] [Full Text: https://doi.org/10.1086/316904]
Sakai, K., Hirai, M., Minoshima, S., Kudoh, J., Fukuyama, R., Shimizu, N. Isolation of cDNAs encoding a substrate for protein kinase C: nucleotide sequence and chromosomal mapping of the gene for a human 80K protein. Genomics 5: 309-315, 1989. [PubMed: 2793184] [Full Text: https://doi.org/10.1016/0888-7543(89)90063-3]
Trombetta, E. S., Simons, J. F., Helenius, A. Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, and a tightly bound noncatalytic HDEL-containing subunit. J. Biol. Chem. 271: 27509-27516, 1996. [PubMed: 8910335] [Full Text: https://doi.org/10.1074/jbc.271.44.27509]