Gene Summary

Gene:PRKCSH; protein kinase C substrate 80K-H
Aliases: GIIB, PCLD, PLD1, G19P1, PCLD1, PKCSH, AGE-R2, VASAP-60
Summary:This gene encodes the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum. The encoded protein is an acidic phosphoprotein known to be a substrate for protein kinase C. Mutations in this gene have been associated with the autosomal dominant polycystic liver disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glucosidase 2 subunit beta
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Mutation
  • Single Nucleotide Polymorphism
  • Phosphoproteins
  • Endoplasmic Reticulum
  • alpha-Glucosidases
  • TRPP Cation Channels
  • Liver
  • Polycystic Kidney, Autosomal Dominant
  • beta Catenin
  • Transfection
  • Ultrasonography
  • Phenotype
  • Wnt Signaling Pathway
  • DNA Mutational Analysis
  • Cell Surface Receptors
  • Cysts
  • Membrane Proteins
  • Signal Transduction
  • Low Density Lipoprotein Receptor-Related Protein-5
  • X-Ray Computed Tomography
  • Liver Diseases
  • Alleles
  • Pedigree
  • Amino Acid Sequence
  • Loss of Heterozygosity
  • Young Adult
  • Sequence Homology
  • Polymorphism
  • Molecular Sequence Data
  • Sequence Deletion
  • Trinucleotide Repeats
  • Trisomy
  • Intracellular Signaling Peptides and Proteins
  • Heterozygote
  • Chromosome 19
  • Germ-Line Mutation
  • Glucosidases
  • Genotype
  • SEC Translocation Channels
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: PRKCSH (cancer-related)

Zhang M, Srichai MB, Zhao M, et al.
Nonselective Cyclooxygenase Inhibition Retards Cyst Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease.
Int J Med Sci. 2019; 16(1):180-188 [PubMed] Free Access to Full Article Related Publications

Toteda G, Vizza D, Lupinacci S, et al.
Olive leaf extract counteracts cell proliferation and cyst growth in an in vitro model of autosomal dominant polycystic kidney disease.
Food Funct. 2018; 9(11):5925-5935 [PubMed] Related Publications
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts, leading to chronic kidney disease. Since the available treatment for ADPKD is limited, there is emerging interest for natural compounds as potential therapeutic candidates. The aim of our study was to investigate whether an olive leaf extract may be able to counteract the cyst growth in an in vitro model of ADPKD. We treated WT9-12 cells with an olive leaf extract (OLE). In monolayer culture we evaluated cell viability by the MTT assay, protein expression by western-blot analysis and apoptosis by DNA laddering and TUNEL assays. For functional studies we used transient transfection and ChIP assays. Intracellular calcium measurement was performed with a spectrofluorimeter using a fluorescent probe. 3D-cell-culture was used for cyst growth studies. OLE reduced the WT9-12 cell growth rate and affected intracellular signaling due to high c-AMP levels, as OLE reduced PKA levels, enhanced p-AKT, restored B-Raf-inactivation and down-regulated p-ERK. We elucidated the molecular mechanism by which OLE, via Sp1, transactivates the p21WAF1/Cip1 promoter, whose levels are down-regulated by mutated PKD1. We demonstrated that p-AKT up-regulation also played a crucial role in the OLE-induced anti-apoptotic effect and that OLE ameliorated intracellular calcium levels, the primary cause of ADPKD. Finally, using a 3D-cell-culture model we observed that OLE reduced the cyst size. Therefore, multifaceted OLE may be considered a new therapeutic approach for ADPKD treatment.

Liu JX, Li W, Li JT, et al.
Screening key long non-coding RNAs in early-stage colon adenocarcinoma by RNA-sequencing.
Epigenomics. 2018; 10(9):1215-1228 [PubMed] Related Publications
AIM: We aim to identify the key long noncoding RNAs (lncRNAs) in early-stage colon adenocarcinoma (COAD).
PATIENTS & METHODS: Compared with colonic intraepithelial neoplasia, differentially expressed lncRNAs (DElncRNAs) in early-stage COAD were obtained by RNA-sequencing. Our previous work has obtained the differentially expressed mRNAs and miRNAs (DEmRNAs and DEmiRNAs) in early-stage COAD. DEmiRNA-DElncRNA-DEmRNA interaction analysis and functional annotation were performed. Validation of expression and receiver-operating characteristic analyses were performed based on The Cancer Genome Atlas.
RESULTS: Seventy-nine significantly DElncRNAs in early-stage COAD were obtained. MiR-153-3p-TUG1-DAPK1/ARNT2/KLK3/PLD1/SMAD2 and miR-153-3p-SNHG17-COL11A1/IGFBP3/KLF6 interactions were associated with early-stage COAD. Five DElncRNAs (ELFN1-AS1, LINC01234, SNHG17, UCA1 and LOC101929549) involved in early-stage COAD with potential diagnostic value.
CONCLUSION: LncRNAs involve in early-stage COAD by interaction with COAD-regulated genes and miRNAs.

Kamiya A, Chikada H, Ida K, et al.
An in vitro model of polycystic liver disease using genome-edited human inducible pluripotent stem cells.
Stem Cell Res. 2018; 32:17-24 [PubMed] Related Publications
In the developing liver, bile duct structure is formed through differentiation of hepatic progenitor cells (HPC) into cholangiocytes. A subtype of polycystic liver diseases characterized by uncontrolled expansion of bile ductal cells is caused by genetic abnormalities such as in that of protein kinase C substrate 80 K-H (PRKCSH). In this study, we aimed to mimic the disease process in vitro by genome editing of the PRKCSH locus in human inducible pluripotent stem (iPS) cells. A proportion of cultured human iPS cell-derived CD13

Stumm J, Vallecillo-García P, Vom Hofe-Schneider S, et al.
Odd skipped-related 1 (Osr1) identifies muscle-interstitial fibro-adipogenic progenitors (FAPs) activated by acute injury.
Stem Cell Res. 2018; 32:8-16 [PubMed] Related Publications
Fibro-adipogenic progenitors (FAPs) are resident mesenchymal progenitors in adult skeletal muscle that support muscle repair, but also give rise to fibrous and adipose infiltration in response to disease and chronic injury. FAPs are identified using cell surface markers that do not distinguish between quiescent FAPs and FAPs actively engaged in the regenerative process. We have shown previously that FAPs are derived from cells that express the transcription factor Osr1 during development. Here we show that adult FAPs express Osr1 at low levels and frequency, however upon acute injury FAPs reactivate Osr1 expression in the injured tissue. Osr1

Kanai T, Shiizaki K, Betsui H, et al.
A decreased soluble Klotho level with normal eGFR, FGF23, serum phosphate, and FEP in an ADPKD patient with enlarged kidneys due to multiple cysts.
CEN Case Rep. 2018; 7(2):259-263 [PubMed] Free Access to Full Article Related Publications
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. ADPKD is characterized clinically by the presence of multiple bilateral renal cysts that lead to chronic renal failure. The cysts evolve from renal tubular epithelial cells that express the Klotho gene. Notably, Klotho acts as a co-receptor for fibroblast growth factor 23 (FGF23); in this context, it induces phosphaturia and maintains serum phosphate at a normal level. Many reports have shown that decreases in the soluble Klotho level and increases in the FGF23 level are associated with glomerular filtration rate (GFR) decline, but a recent study observed these changes in patient with normal eGFR. It remains unclear whether the decrease in the Klotho level precedes the increase in FGF23. Here, we present an ADPKD patient with enlarged kidneys due to multiple cysts who had a decreased soluble Klotho level but a normal eGFR and a normal FGF23 level. The patient's serum phosphate level was normal, as was the fractional excretion of phosphate (FEP). This appears to be the first reported case to show a decreased soluble Klotho level plus normal eGFR, FGF23, and FEP. These results suggest that Klotho decreases before FGF23 increases and further suggest that Klotho is not required to maintain normal serum phosphate levels in ADPKD if the FEP and serum phosphate levels are normal.

Kandori S, Kojima T, Matsuoka T, et al.
Phospholipase D2 promotes disease progression of renal cell carcinoma through the induction of angiogenin.
Cancer Sci. 2018; 109(6):1865-1875 [PubMed] Free Access to Full Article Related Publications
A hallmark of clear cell renal cell carcinoma (ccRCC) is the presence of intracellular lipid droplets (LD) and it is assumed that phosphatidic acid (PA) produced by phospholipase D (PLD) plays some role in the LD formation. However, little is known about the significance of PLD in ccRCC. In this study, we examined the expression levels of PLD in ccRCC. The classical mammalian isoforms of PLD are PLD1 and PLD2, and the levels of both mRNA were higher at the primary tumor sites than in normal kidney tissues. Similarly, both PLD were significantly abundant in tumor cells as determined by analysis using immunohistochemical staining. Importantly, a higher level of PLD was significantly associated with a higher tumor stage and grade. Because PLD2 knockdown effectively suppressed the cell proliferation and invasion of ccRCC as compared with PLD1 in vitro, we examined the effect of PLD2 in vivo. Notably, shRNA-mediated knockdown of PLD2 suppressed the growth and invasion of tumors in nude mouse xenograft models. Moreover, the higher expression of PLD2 was significantly associated with poorer prognosis in 67 patients. As for genes relating to the tumor invasion of PLD2, we found that angiogenin (ANG) was positively regulated by PLD2. In fact, the expression levels of ANG were elevated in tumor tissues as compared with normal kidney and the inhibition of ANG activity with a neutralizing antibody significantly suppressed tumor invasion. Overall, we revealed for the first time that PLD2-produced PA promoted cell invasion through the expression of ANG in ccRCC cells.

Rauscher B, Heigwer F, Henkel L, et al.
Toward an integrated map of genetic interactions in cancer cells.
Mol Syst Biol. 2018; 14(2):e7656 [PubMed] Free Access to Full Article Related Publications
Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and create vulnerabilities for potential therapeutic exploitation. To identify genotype-dependent vulnerabilities, forward genetic screens in different genetic backgrounds have been conducted. We devised MINGLE, a computational framework to integrate CRISPR/Cas9 screens originating from different libraries building on approaches pioneered for genetic network discovery in model organisms. We applied this method to integrate and analyze data from 85 CRISPR/Cas9 screens in human cancer cells combining functional data with information on genetic variants to explore more than 2.1 million gene-background relationships. In addition to known dependencies, we identified new genotype-specific vulnerabilities of cancer cells. Experimental validation of predicted vulnerabilities identified GANAB and PRKCSH as new positive regulators of Wnt/β-catenin signaling. By clustering genes with similar genetic interaction profiles, we drew the largest genetic network in cancer cells to date. Our scalable approach highlights how diverse genetic screens can be integrated to systematically build informative maps of genetic interactions in cancer, which can grow dynamically as more data are included.

Besse W, Choi J, Ahram D, et al.
A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.
Hum Mutat. 2018; 39(3):378-382 [PubMed] Free Access to Full Article Related Publications
Expanded mutation detection and novel gene discovery for isolated polycystic liver disease (PCLD) are necessary as 50% of cases do not have identified mutations in the seven published disease genes. We investigated a family with five affected siblings for which no loss-of-function variants were identified by whole exome sequencing analysis. SNP genotyping and linkage analysis narrowed the candidate regions to ∼8% of the genome, which included two published PCLD genes in close proximity to each other, GANAB and LRP5. Based on these findings, we re-evaluated the exome sequencing data and identified a novel intronic nine base pair deletion in the vicinity of the GANAB exon 24 splice donor that had initially been discarded by the sequence analysis pipelines. We used a minigene assay to show that this deletion leads to skipping of exon 24 in cell lines and primary human cholangiocytes. These findings prompt genomic evaluation beyond the coding region to enhance mutation detection in PCLD and to avoid premature implication of other genes in linkage disequilibrium.

Cornec-Le Gall E, Torres VE, Harris PC
Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases.
J Am Soc Nephrol. 2018; 29(1):13-23 [PubMed] Free Access to Full Article Related Publications
Data indicate significant phenotypic and genotypic overlap, plus a common pathogenesis, between two groups of inherited disorders, autosomal dominant polycystic kidney diseases (ADPKD), a significant cause of ESRD, and autosomal dominant polycystic liver diseases (ADPLD), which result in significant PLD with minimal PKD. Eight genes have been associated with ADPKD (

Ishimoto Y, Inagi R, Yoshihara D, et al.
Mitochondrial Abnormality Facilitates Cyst Formation in Autosomal Dominant Polycystic Kidney Disease.
Mol Cell Biol. 2017; 37(24) [PubMed] Free Access to Full Article Related Publications
Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the

Santos SF, Francisco T, Cordeiro AI, Lopes MJP
Beyond polycystic kidney disease.
BMJ Case Rep. 2017; 2017 [PubMed] Free Access to Full Article Related Publications
Tuberous sclerosis(TS) is an autosomal dominant disease caused by mutations in

Wills ES, Te Morsche RHM, van Reeuwijk J, et al.
Liver cyst gene knockout in cholangiocytes inhibits cilium formation and Wnt signaling.
Hum Mol Genet. 2017; 26(21):4190-4202 [PubMed] Related Publications
Mutations in the PRKCSH, SEC63 and LRP5 genes cause autosomal dominant polycystic liver disease (ADPLD). The proteins products of PRKCSH (alias GIIB) and SEC63 function in protein quality control and processing in the endoplasmic reticulum (ER), while LRP5 is implicated in Wnt/β-catenin signaling. To identify common denominators in the PLD pathogenesis, we mapped the PLD interactome by affinity proteomics, employing both HEK293T cells and H69 cholangiocytes. Identification of known complex members, such as glucosidase IIA (GIIA) for PRKCSH, and SEC61A1 and SEC61B for SEC63, confirmed the specificity of the analysis. GANAB, encoding GIIA, was very recently identified as an ADPLD gene. The presence of GIIA in the LRP5 complex pinpoints a potential functional connection with PRKCSH. Interestingly, all three PLD-associated protein complexes included filamin A (FLNA), a multifunctional protein described to play a role in ciliogenesis as well as canonical Wnt signalling. As ciliary dysfunction may also contribute to hereditary liver cyst formation, we evaluated the requirement of PRKCSH and SEC63 for ciliogenesis and Wnt signaling. By CRISPR/Cas9 induced knockdown of both ADPLD genes in HEK293T cells and H69 cholangiocytes, we identified that their depletion results in defective ciliogenesis. However, only H69 knockouts displayed reduced Wnt3a activation. Our results suggest that loss of PRKCSH and SEC63 leads to general defects in ciliogenesis, while quenching of the Wnt signaling cascade is cholangiocyte-restricted. Interactions of all three PLD-associated protein complexes with FLNA may mark a common link between the ADPLD proteins and the cystogenic processes driving this disease.

Kang DW, Lee BH, Suh YA, et al.
Phospholipase D1 Inhibition Linked to Upregulation of ICAT Blocks Colorectal Cancer Growth Hyperactivated by Wnt/β-Catenin and PI3K/Akt Signaling.
Clin Cancer Res. 2017; 23(23):7340-7350 [PubMed] Related Publications

Khaodee W, Inboot N, Udomsom S, et al.
Glucosidase II beta subunit (GluIIβ) plays a role in autophagy and apoptosis regulation in lung carcinoma cells in a p53-dependent manner.
Cell Oncol (Dordr). 2017; 40(6):579-591 [PubMed] Related Publications
PURPOSE: Glucosidase II plays a major role in regulating the post-translational modification of N-linked glycoproteins. Previously, we found that the beta subunit of glucosidase II (GluIIβ) levels are significantly increased in lung carcinoma tissues, indicating a potential role in lung tumorigenesis. Here, we investigated the role of GluIIβ in the regulation of autophagy and apoptosis in lung carcinoma- and immortalized human bronchial epithelial-derived cells.
METHODS: A selective glucosidase II inhibitor, bromoconduritol, was used to inhibit GluII enzyme activity and a siRNA-based technology was used to suppress the expression of the GluIIβ encoding gene PRKCSH in lung carcinoma cells differing in p53 status. Cell viability was assessed using a MTT assay, cell cycle progression was assessed using flow cytometry, autophagy was assessed using Western blotting and apoptosis was assessed using an annexin V-FITC/PI double labeling method.
RESULTS: We found that GluIIβ inhibition resulted in the induction of autophagy in all cell lines tested, but apoptosis in only wild-type p53 cells. We also found that GluIIβ inhibition dose-dependently decreased activation of the EGFR/RTK and PI3K/AKT signaling pathways. Although the apoptosis inducing effect of GluIIβ inhibition appeared to be p53-dependent, we found that a combined treatment with lysosomal inhibitors to block autophagy enhanced the apoptotic effect of GluIIβ inhibition in both wild-type p53 and p53-null cells.
CONCLUSIONS: Our data indicate that GluIIβ inhibition results in autophagy and apoptosis in lung carcinoma-derived cells, supporting the hypothesis that this enzyme may play a role in blocking these two tumor suppressive processes. Since blocking autophagy by lysosomal inhibitors enhanced the apoptosis-inducing effect of bromoconduritol, independent of p53 status, their combined use may hold promise for the treatment of cancer, particularly lung cancer.

Temmerman F, Chen F, Libbrecht L, et al.
Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease.
World J Gastroenterol. 2017; 23(30):5499-5507 [PubMed] Free Access to Full Article Related Publications
AIM: To develop a MRI-based method for accurate determination of liver volume (LV) and to explore the effect of long-term everolimus (EVR) treatment on LV in PCK rats with hepatomegaly.
METHODS: Thirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease). Animals received: controls (
RESULTS: LV determination by MRI correlated excellent with the
CONCLUSION: Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. mTOR-inhibition should be further explored in PCLD patients especially those that need immunosuppression.

van de Laarschot LFM, Drenth JPH
Genetics and mechanisms of hepatic cystogenesis.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(4 Pt B):1491-1497 [PubMed] Related Publications
Polycystic liver disease (PLD) is a heterogeneous genetic condition. PKD1 and PKD2 germline mutations are found in patients with autosomal dominant polycystic kidney disease (ADPKD). Autosomal dominant polycystic liver disease (ADPLD) is associated with germline mutations in PRKCSH, SEC63, LRP5, and recently ALG8 and SEC61. GANAB mutations are found in both patient groups. Loss of heterozygosity of PLD-genes in cyst epithelium contributes to the development of hepatic cysts. A genetic interaction network is implied in hepatic cystogenesis that connects the endoplasmic glycoprotein control mechanisms and polycystin expression and localization. Wnt signalling could be the major downstream signalling pathway that results in hepatic cyst growth. PLD in ADPLD and ADPKD probably results from changes in one common final pathway that initiates cyst growth. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Lu M, Song Y, Fu W, et al.
MicroRNA and target mRNA selection through invasion and cytotoxicity cell modeling and bioinformatics approaches in esophageal squamous cell carcinoma.
Oncol Rep. 2017; 38(2):1181-1189 [PubMed] Related Publications
This study analyzed microRNA (miRNA) and mRNA expression profiles and investigated the biological characteristics of ESCC by using invasion and cytotoxicity cell models. miRNA profiles were evaluated through miRNA microarray. Transwell chamber and nedaplatin (NDP) were used to construct invasion and cytotoxicity cell models. Invasion Transwell and cytotoxicity assays were performed to examine the invasiveness and proliferation in the cell models. Functional miRNAs were selected from dysregulated miRNAs through qRT-PCR. Biometric Research Program (BRB)-array tools, Cytoscape plugins, and DAVID were utilized to find potential mRNAs targeted by these two miRNAs between ESCC and paired normal adjacent tissues. Our microarray obtained 11 dysregulated miRNAs expressed in three paired ESCC samples from Kazakhs (ethnicity in Northwestern China). qRT-PCR demonstrated the miRNA expression in the invasion and cytotoxicity cell models. miR‑652-5p and miR‑21‑5p exhibited a consistent expression level in the microarray and cell models. Bioinformatics revealed that the potential targets of PLD1, MSH2, STC1, and DSG1 might be involved in ESCC invasion and proliferation. Cell models with bioinformatics approaches may help distinguish functional genes. miR‑652-5p, miR‑21‑5p, and their potential target genes may participate in ESCC development and metastasis.

Cheng M, Rizwan A, Jiang L, et al.
Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer.
Neoplasia. 2017; 19(8):617-627 [PubMed] Free Access to Full Article Related Publications
Abnormal choline phospholipid metabolism is a hallmark of cancer. The magnetic resonance spectroscopy (MRS) detected total choline (tCho) signal can serve as an early noninvasive imaging biomarker of chemotherapy response in breast cancer. We have quantified the individual components of the tCho signal, glycerophosphocholine (GPC), phosphocholine (PC) and free choline (Cho), before and after treatment with the commonly used chemotherapeutic drug doxorubicin in weakly metastatic human MCF7 and triple-negative human MDA-MB-231 breast cancer cells. While the tCho concentration did not change following doxorubicin treatment, GPC significantly increased and PC decreased. Of the two phosphatidylcholine-specific PLD enzymes, only PLD1, but not PLD2, mRNA was down-regulated by doxorubicin treatment. For the two reported genes encoding GPC phosphodiesterase, the mRNA of GDPD6, but not GDPD5, decreased following doxorubicin treatment. mRNA levels of choline kinase α (ChKα), which converts Cho to PC, were reduced following doxorubicin treatment. PLD1 and ChKα protein levels decreased following doxorubicin treatment in a concentration dependent manner. Treatment with the PLD1 specific inhibitor VU0155069 sensitized MCF7 and MDA-MB-231 breast cancer cells to doxorubicin-induced cytotoxicity. Low concentrations of 100 nM of doxorubicin increased MDA-MB-231 cell migration. GDPD6, but not PLD1 or ChKα, silencing by siRNA abolished doxorubicin-induced breast cancer cell migration. Doxorubicin induced GPC increase and PC decrease are caused by reductions in PLD1, GDPD6, and ChKα mRNA and protein expression. We have shown that silencing or inhibiting these genes/proteins can promote drug effectiveness and reduce adverse drug effects. Our findings emphasize the importance of detecting PC and GPC individually.

Siroky BJ, Towbin AJ, Trout AT, et al.
Improvement in Renal Cystic Disease of Tuberous Sclerosis Complex After Treatment with Mammalian Target of Rapamycin Inhibitor.
J Pediatr. 2017; 187:318-322.e2 [PubMed] Related Publications
Renal cysts occur in approximately 50% of patients with tuberous sclerosis complex, but their clinical significance and response to treatment are unknown. Abdominal imaging of 15 patients with tuberous sclerosis complex-associated renal cystic disease who had received mammalian target of rapamycin inhibitor therapy for other tuberous sclerosis complex-related indications was evaluated. Reductions in cyst number, sum diameter, and volume were observed.

Besse W, Dong K, Choi J, et al.
Isolated polycystic liver disease genes define effectors of polycystin-1 function.
J Clin Invest. 2017; 127(5):1772-1785 [PubMed] Free Access to Full Article Related Publications
Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.

Ma M, Gallagher AR, Somlo S
Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease.
Cold Spring Harb Perspect Biol. 2017; 9(11) [PubMed] Related Publications
Autosomal-dominant polycystic kidney disease (ADPKD) is a disease of defective tissue homeostasis resulting in active remodeling of nephrons and bile ducts to form fluid-filled sacs called cysts. The causal genes

Lai J, Modi L, Ramai D, Tortora M
Tuberous sclerosis complex and polycystic kidney disease contiguous gene syndrome with Moyamoya disease.
Pathol Res Pract. 2017; 213(4):410-415 [PubMed] Related Publications
Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are two diseases sharing close genetic loci on chromosome 16. Due to contiguous gene syndrome, also known as contiguous gene deletion syndrome, the proximity of TSC2 and PKD1 genes increases the risk of co-deletion resulting in a shared clinical presentation. Furthermore, Moyamoya disease (MMD) is a rare vaso-occlusive disease in the circle of Willis. We present the first case of TSC2/PKD1 contiguous gene syndrome in a patient with MMD along with detailed histopathologic, radiologic, and cytogenetic analyses. We also highlight the clinical presentation and surgical complications in this case.

Lian M, Shi Q, Fang J, et al.
In vivo gene expression profiling for chemosensitivity to docetaxel-cisplatin-5-FU (TPF) triplet regimen in laryngeal squamous cell carcinoma and the effect of TPF treatment on related gene expression in vitro.
Acta Otolaryngol. 2017; 137(7):765-772 [PubMed] Related Publications
CONCLUSION: These results provided a battery of genes relating to TPF chemotherapeutic sensitivity and might act as molecular targets in laryngeal squamous cell carcinoma (LSCC) treatment. Moreover, these candidate biomarkers could contribute to LSCC individualized treatment.
OBJECTIVES: To screen out a set of candidate genes which could help to determine whether patients with LSCC could benefit from TPF induction chemotherapy.
METHOD: Gene-expression profiles in seven TPF-sensitive patients were compared to four resistant controls by microarray analysis. Subsequently, expression levels of potential biomarkers in chemosensitive cell line UMSCC5 after TPF treatment were observed by qRT-PCR.
RESULTS: Through microarray analysis, 1546 differently expressed genes were identified, of which 769 were up-regulated in TPF chemotherapy-responsive tissues, whereas 777 were down-regulated. Gene ontology (GO) analysis suggested these genes participating in physiological processes including cell differentiation, metabolism, signal transduction, and cellular component organization. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed that Wnt and p53 signaling pathways occupied important roles in TPF chemotherapeutic sensitivity. Moreover, in vitro cell culture experiments revealed the expression alternations of Mapk10, Jun, Vegfb, Pik3r5, Pld1, Tek, Itga6 exposed to TPF treatment by qRT-PCR, whilst providing an insight into the mechanism underlying TPF chemotherapeutic response in LSCC.

Henkels KM, Muppani NR, Gomez-Cambronero J
PLD-Specific Small-Molecule Inhibitors Decrease Tumor-Associated Macrophages and Neutrophils Infiltration in Breast Tumors and Lung and Liver Metastases.
PLoS One. 2016; 11(11):e0166553 [PubMed] Free Access to Full Article Related Publications
Phospholipase D-2 (PLD2) has a key role in breast cancer formation and metastasis formation with PLD small inhibitors reducing primary tumor growth. This study aimed to evaluate the importance of targeting PLD on the tumor microenvironment. We provide evidence about the beneficial effect of PLD inhibitors [FIPI (dual PLD1/PLD2) or VU0155072-2 (PLD2 inhibitor)] on avoiding infiltration of tumor-helping macrophages and neutrophils. Tumor growth and metastasis within the primary tumors had low (<20% over controls) PLD enzyme activity. Unexpectedly, we found that the inhibitors also affected PLD2 gene expression and protein albeit at a lesser extent. The later could indicate that targeting both the actual PLD enzyme and its activity could be beneficial for potential cancer treatments in vivo. F4/80 and Ly6G staining of macrophages and neutrophils, respectively, and Arg1 staining data were consistent with M2 and N2 polarization. NOS2 staining increased in xenotransplants upon treatment with PLD2 inhibitors suggesting the novel observation that an increased recruitment of M1 macrophages occurred in primary tumors. PLD inhibitor-treated primary tumors had large, fragile, necrotic areas that were Arg1+ for M2 macrophages. The xenotransplants also caused the formation of large F4/80+ and Ly6G+ (>100 μm) clusters in lungs. However, PLD inhibitors, particularly FIPI, were able to diminish leukocyte presence. Ex vivo chemotaxis and PLD activity of peripheral blood neutrophils (PMN) and peritoneal macrophages was also determined. Whereas PMN had impaired functionality, macrophages did not. This significantly increased ("emboldened") macrophage function was due to PLD inhibition. Since tumor-associated leukocytes in primary tumors and metastases were targeted via PLD inhibition, we posit that these inhibitors have a key role in cancer regression, while still affording an appropriate inflammatory response at least from off-site innate immunity macrophages.

Belmonte JM, Clendenon SG, Oliveira GM, et al.
Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease.
Mol Biol Cell. 2016; 27(22):3673-3685 [PubMed] Free Access to Full Article Related Publications
In autosomal dominant polycystic kidney disease (ADPKD), cysts accumulate and progressively impair renal function. Mutations in PKD1 and PKD2 genes are causally linked to ADPKD, but how these mutations drive cell behaviors that underlie ADPKD pathogenesis is unknown. Human ADPKD cysts frequently express cadherin-8 (cad8), and expression of cad8 ectopically in vitro suffices to initiate cystogenesis. To explore cell behavioral mechanisms of cad8-driven cyst initiation, we developed a virtual-tissue computer model. Our simulations predicted that either reduced cell-cell adhesion or reduced contact inhibition of proliferation triggers cyst induction. To reproduce the full range of cyst morphologies observed in vivo, changes in both cell adhesion and proliferation are required. However, only loss-of-adhesion simulations produced morphologies matching in vitro cad8-induced cysts. Conversely, the saccular cysts described by others arise predominantly by decreased contact inhibition, that is, increased proliferation. In vitro experiments confirmed that cell-cell adhesion was reduced and proliferation was increased by ectopic cad8 expression. We conclude that adhesion loss due to cadherin type switching in ADPKD suffices to drive cystogenesis. Thus, control of cadherin type switching provides a new target for therapeutic intervention.

Ta-Shma A, Zhang K, Salimova E, et al.
Congenital valvular defects associated with deleterious mutations in the
J Med Genet. 2017; 54(4):278-286 [PubMed] Related Publications
BACKGROUND: The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families.
METHODS: Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D (
RESULTS: Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the
CONCLUSIONS: The findings support a role for PLD1 in normal heart valvulogenesis.

Kang DW, Lee SW, Hwang WC, et al.
Phospholipase D1 Acts through Akt/TopBP1 and RB1 to Regulate the E2F1-Dependent Apoptotic Program in Cancer Cells.
Cancer Res. 2017; 77(1):142-152 [PubMed] Related Publications
The RB1/E2F1 signaling pathway is frequently deregulated in colorectal cancer and has been suggested to intersect with Wnt/β-catenin and PI3K/Akt pathways, but molecular evidence for this link is lacking. In this study, we demonstrate that phospholipase D1 (PLD1), a transcriptional target of β-catenin/TCF4, orchestrates functional interactions between these pathways during intestinal tumor development. Overexpression of PLD1 in intestinal epithelial cells protected cells from apoptosis induced by PLD1 ablation in the Apc

Hitchcock E, Gibson WT
A Review of the Genetics of Intracranial Berry Aneurysms and Implications for Genetic Counseling.
J Genet Couns. 2017; 26(1):21-31 [PubMed] Free Access to Full Article Related Publications
Here we review the current understanding of the genetic architecture of intracranial berry aneurysms (IBA) to aid in the genetic counseling of patients at risk for this condition. The familial subtype of IBA, familial intracranial aneurysms (FIA), is associated with increased frequency of IBA, increased risk of rupture, and increased morbidity and mortality after rupture. Family history is the strongest predictor for the development of IBA. However, a genetic test is not yet available to assess risk within a family. Studies using linkage analysis, genome-wide association, and next-generation sequencing have found several candidate loci and genes associated with disease onset, but have not conclusively implicated a single gene. In addition to family history, a separate or concurrent diagnosis of autosomal dominant polycystic kidney disease is a strong genetic risk factor for IBA formation. We also discuss the relative risk for developing IBA in several Mendelian syndromes including vascular Ehlers-Danlos syndrome, Marfan syndrome, Neurofibromatosis Type I, and Loeys-Dietz syndrome.

D'Agnolo HM, Kievit W, van Munster KN, et al.
Center is an important indicator for choice of invasive therapy in polycystic liver disease.
Transpl Int. 2017; 30(1):76-82 [PubMed] Related Publications
Polycystic liver disease (PLD) is a rare genetic disorder with progressive cyst growth as the primary phenotype. Therapy consists of volume reduction through invasive surgical or radiological procedures. To understand the process of treatment decision, our aim was to identify factors that increased the likelihood of treatment. We performed a cross-sectional study using an international population of patients with PLD. We collected data on the following therapies: liver transplantation, resection, fenestration, and aspiration sclerotherapy. Data on the potential determinants, sex, center, autosomal dominant polycystic kidney disease (ADPKD), autosomal dominant polycystic liver disease (ADPLD), age at diagnosis, symptoms, and phenotype, were included. We corrected for follow-up time. We included 578 patients in our study, and 35% underwent invasive therapy. Multivariate regression analysis showed that number of symptoms and age at diagnosis of PLD increased the likelihood of treatment (respectively, RR: 1.4, P < 0.001 and RR = 1.4, P = 0.03). The choice for liver transplantation or aspiration sclerotherapy was center dependent (RR: 0.7, P < 0.001 and RR: 1.1, P = 0.03, respectively). The results of our international cross-sectional study suggest that a higher number of symptoms and every 10 years of PLD diagnosis increase the risk to undergo treatment by 40%. The choice to elect a particular modality is center dependent.

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