Detection of PKD1 and PKD2 Somatic Variants in Autosomal Dominant Polycystic Kidney Cyst Epithelial Cells by Whole-Genome Sequencing

2021 ◽  
pp. ASN.2021050690
Author(s):  
Zhengmao Zhang ◽  
Hanwen Bai ◽  
Jon Blumenfeld ◽  
Andrew Ramnauth ◽  
Irina Barash ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Fragile Sites ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Polycystic Kidney ◽  
Second Hit ◽  
Kidney Cyst ◽  
Kidney Cysts ◽  
Autosomal Dominant Polycystic Kidney

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of multiple cysts in the kidneys. It is often caused by pathogenic mutations in PKD1 and PKD2 genes that encode polycystin proteins. Although the molecular mechanisms for cystogenesis are not established, concurrent inactivating germline and somatic mutations in PKD1 and PKD2 have been previously observed in renal tubular epithelium (RTE). Methods: To further investigate the cellular recessive mechanism of cystogenesis in RTE, we conducted whole-genome DNA sequencing analysis to identify germline variants and somatic alterations in RTE of 90 unique kidney cysts obtained during nephrectomy from 24 unrelated participants. Results: Kidney cysts were overall genomically stable, with low burdens of somatic short mutations or large-scale structural alterations. Pathogenic somatic "second hit" alterations disrupting PKD1 or PKD2 were identified in 93% of the cysts. Of these, 77% of cysts acquired short mutations in PKD1 or PKD2; specifically, 60% resulted in protein truncations (nonsense, frameshift, or splice site) and 16.7% caused non-truncating mutations (missense, in-frame insertions, or deletions). Another ~18% of cysts acquired somatic chromosomal loss of heterozygosity (LOH) events encompassing PKD1 or PKD2 ranging from 2.6 to 81.3 Mb. 14.4% of these cysts harbored copy number neutral LOH events, while the other 3.3% had hemizygous chromosomal deletions. LOH events frequently occurred at chromosomal fragile sites, or in regions comprising chromosome microdeletion diseases/syndromes. Almost all somatic "second hit" alterations occurred at the same germline mutated PKD1/2 gene. Conclusions: These findings further support a cellular recessive mechanism for cystogenesis in ADPKD primarily caused by inactivating germline and somatic variants of PKD1 or PKD2 genes in kidney cyst epithelium.

Diagnosis of infected kidney cysts in patients with autosomal dominant polycystic kidney disease and end-stage renal disease

Urologiia ◽  
2021 ◽  
Vol 3_2021 ◽  
pp. 50-55
Author(s):  
A.E. Lubennikov Lubennikov ◽  
A.A. Shishimorov Shishimorov ◽  
R.N. Trushkin Trushkin ◽  
T.K. Isaev T ◽  
O.N. Kotenko Kotenko ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Polycystic Kidney Disease ◽  
End Stage Renal Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Kidney Cysts ◽  
Autosomal Dominant Polycystic Kidney ◽  
Stage Renal Disease ◽  
End Stage

scholarly journals FP064ASSOCIATION BETWEEN POLYCYSTIC LIVER CYST AND KIDNEY CYST IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

2018 ◽  
Vol 33 (suppl_1) ◽  
pp. i69-i69
Author(s):  
Hiroki Mizuno ◽  
Junichi Hoshino ◽  
Yoshifumi Ubara ◽  
Masahiko Oguro ◽  
Akinari Sekine ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Liver Cyst ◽  
Polycystic Kidney ◽  
Kidney Cyst ◽  
Polycystic Liver ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Examining the Role of HIPPO/YAP and AMOT Dysregulation and Imbalance in Autosomal Dominant Polycystic Kidney Disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
John Underwood ◽  
Robert L. Bacallao
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Ectopic Expression ◽  
Renal Dialysis ◽  
National Institutes Of Health ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder, most commonly caused by mutations in Polycystin-1 and Polycystin-2 (PC1 and PC2), in which many large lumenal cysts develop in the kidney epithelium. The disease is progressive and ultimately leads to renal dialysis and/or kidney transplant given the lack of efficacious therapeutic intervention. Current research has implicated HIPPO/YAP pathway dysregulation and AMOT imbalance following defects in cell-cell adhesion and contact inhibition as the molecular basis for ADPKD. To test this hypothesis as to the minimum cellular changes necessary to produce cystogenesis, the Bacallao lab microinjected normal human kidney epithelial (HK2) cells in order to drive ectopic expression of Cadherin-8 (CAD-8). Our Imaging with confocal microscopy and subsequent image analysis indicates CAD-8, a cadherin abnormally expressed in renal epithelial cells of ADPKD patients, is sufficient to cause formation of cysts albeit with uncharacteristically small lumens compared to typical ADPKD cysts. However, these cells exhibit significantly larger cyst expansion when they are transduced for coexpression of CAD-8 and constitutively active YAP5SA. Cells modified for heterozygosity with respect to a defective PC1 gene (PKD) also exhibited significantly larger lumen cysts when transduced with YAP5SA reinforcing the role of Yap in lumen size control. Finally, PKD cells transduced with AMOTL1 exhibited significantly smaller lumen sizes. AMOTL1 belongs to a family of adapter proteins which bind and inhibit Yap activity thus showing conclusively that positive and negative modulation of Yap activity correlates with cyst lumen size expansion and reduction respectively. “This project was funded, in part, with support from the O’Brien Center for Advanced Renal Microscopic Analysis funded, in part by P30 DK079312 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.”

scholarly journals Role of DNA-Dependent Protein Kinase in Mediating Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

2021 ◽  
Vol 22 (19) ◽  
pp. 10512
Author(s):  
Ashley N. Chandra ◽  
Sayanthooran Saravanabavan ◽  
Gopala K. Rangan
Keyword(s):  
Protein Kinase ◽  
Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Dependent Protein Kinase ◽  
Kidney Cyst ◽  
Dependent Protein ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein involved in DNA damage response (DDR) signaling that may mediate kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD) due to its pleiotropic effects on proliferation and survival. To test this hypothesis, the expression of DNA-PK in human ADPKD and the in vitro effects of DNA-PK inhibition in a three-dimensional model of Madin-Darby Canine Kidney (MDCK) cyst growth and human ADPKD cells were assessed. In human ADPKD, the mRNA expression for all three subunits of the DNA-PK complex was increased, and using immunohistochemistry, the catalytic subunit (DNA-PKcs) was detected in the cyst lining epithelia of human ADPKD, in a focal manner. In vitro, NU7441 (a DNA-PK kinase inhibitor) reduced MDCK cyst growth by up to 52% after long-term treatment over 6–12 days. Although human ADPKD cell lines (WT9-7/WT9-12) did not exhibit synthetic lethality in response to DNA-PK kinase inhibition compared to normal human kidney cells (HK-2), the combination of low-dose NU7441 enhanced the anti-proliferative effects of sirolimus in WT9-7 and WT9-12 cells by 17 ± 10% and 11 ± 7%, respectively. In conclusion, these preliminary data suggest that DNA-PK mediates kidney cyst growth in vivo without a synthetically lethal interaction, conferring cell-specificity in human ADPKD cells. NU7441 enhanced the anti-proliferative effects of rapamycin complex 1 inhibitors, but the effect was modest.

Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease

NEJM Evidence ◽  
2021 ◽  
Author(s):  
Gopala K. Rangan ◽  
Annette T.Y. Wong ◽  
Alexandra Munt ◽  
Jennifer Q.J. Zhang ◽  
Sayanthooran Saravanabavan ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Arginine Vasopressin ◽  
Autosomal Dominant ◽  
Urine Osmolality ◽  
Polycystic Kidney ◽  
Vasopressin Release ◽  
Kidney Cyst ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

In patients with autosomal dominant polycystic kidney disease (ADPKD), drinking more water could potentially reduce urine osmolality and suppress arginine vasopressin release and decrease the rate of kidney cyst growth and its associated organ dysfunction. In a 3-year trial, adults with ADPKD randomized to drink more water so as to lower urine osmolality did not have slower kidney growth than did a group who drank water as they wished.

scholarly journals Growth Pattern of Kidney Cyst Number and Volume in Autosomal Dominant Polycystic Kidney Disease

2019 ◽  
Vol 14 (6) ◽  
pp. 823-833 ◽  
Author(s):  
Kyongtae T. Bae ◽  
Wen Zhou ◽  
Chengli Shen ◽  
Douglas P. Landsittel ◽  
Zhiyuan Wu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Growth Pattern ◽  
Autosomal Dominant ◽  
Kidney Volume ◽  
Polycystic Kidney ◽  
Total Kidney Volume ◽  
Cyst Volume ◽  
Kidney Cyst ◽  
Autosomal Dominant Polycystic Kidney ◽  
Over Time

Background and objectivesTo evaluate the growth pattern of kidney cyst number and cyst volume in association with kidney size, demographics, and genotypes in autosomal dominant polycystic kidney disease.Design, setting, participants, & measurementsKidney cyst number and cyst volume were measured from serial magnetic resonance images, giving a maximum follow-up of 14.23 years, from 241 patients with autosomal dominant polycystic kidney disease (15–46 years old at baseline). The growth pattern was analyzed, in association with sex, age, height-adjusted total kidney volume, and genotype, using linear mixed models of repeated measurements and tests of interactions with age (as a time-dependent covariate) to assess rates of change over time. Models were also fit using Irazabal class. Genotypic groups were characterized as either (1) PKD1 truncating, PKD1 nontruncating, and PKD2 plus patients with no mutation detected; or (2) in combination with PKD1 mutation strength groups.ResultsImaging and genetic data were collected (at least one visit) for 236 participants. The mean height-adjusted total cyst number increased exponentially over time from a baseline value of 762 to 1715 at the last clinic visit, while the mean height-adjusted total cyst volume increased exponentially from 305 to 770 ml. Height-adjusted total kidney volume, height-adjusted total cyst number, and height-adjusted total cyst volume were all highly correlated over time. Female participants and participants with larger height-adjusted total kidney volume at baseline showed smaller rates of change in the log of height-adjusted total cyst number and cyst volume. PKD1 was associated with significant increases in both cyst number and volume at a given age, but genotype did not significantly affect the rate of growth.ConclusionsBoth height-adjusted total cyst number and height-adjusted total cyst volume increased exponentially and more than doubled over 14.23 years of follow-up. Compared with PKD2 plus no mutation detected, PKD1 was associated with a greater cyst number and volume at a given age, but no significant difference in the rate of growth.

scholarly journals Primary Aldosteronism in a Patient with Autosomal Dominant Polycystic Kidney Disease Associated with Polycystic Liver Disease

2018 ◽  
Vol 24 (1) ◽  
pp. 55-59
Author(s):  
Pană Camelia ◽  
Fâșie Dragoș ◽  
Voinea Claudia ◽  
Tuță Liliana Ana
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Polycystic Kidney ◽  
Abdominal Ct ◽  
Polycystic Liver ◽  
Abdominal Ct Scan ◽  
Autosomal Dominant Polycystic Kidney ◽  
Low Activity

Abstract Polycystic kidney disease is an autosomal dominant genetic disorder (ADPKD) associated with arterial hypertension, as a common and early manifestation. However, the combination of hypertension and hypokalemia is very rare in these patients and may have another cause. We present a case of a 45 years old man with ADPKD associated with primary hyperaldosteronism. Unilateral suprarenal macroadenoma on abdominal CT scan, severe hypokalemia and low activity of plasmatic renin led to diagnosis.

scholarly journals Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease

2016 ◽  
Vol 24 (11) ◽  
pp. 1584-1590 ◽  
Author(s):  
Amali C Mallawaarachchi ◽  
Yvonne Hort ◽  
Mark J Cowley ◽  
Mark J McCabe ◽  
André Minoche ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Whole Genome Sequencing ◽  
Polycystic Kidney Disease ◽  
Genome Sequencing ◽  
Autosomal Dominant ◽  
Whole Genome ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney
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