The genetic spectrum of polycystic kidney disease in children

SUMMARY OBJECTIVE: Autosomal dominant polycystic kidney disease is an inherited kidney disorder with mutations in polycystin-1 or polycystin-2. Autosomal recessive polycystic kidney disease is a severe form of polycystic kidney disease that is characterized by enlarged kidneys and congenital hepatic fibrosis. Mutations at PKHD1 are responsible for all typical forms of autosomal recessive polycystic kidney disease. METHODS: We evaluated the children diagnosed with polycystic kidney disease between October 2020 and May 2022. The diagnosis was established by family history, ultrasound findings, and/or genetic analysis. The demographic, clinical, and laboratory findings were evaluated retrospectively. RESULTS: There were 28 children (male/female: 11:17) evaluated in this study. Genetic analysis was performed in all patients (polycystin-1 variants in 13, polycystin-2 variants in 7, and no variants in 8 patients). A total of 18 variants in polycystin-1 and polycystin-2 were identified and 9 (50%) of them were not reported before. A total of eight novel variants were identified as definite pathogenic or likely pathogenic mutations. There was no variant detected in the PKDH1 gene. CONCLUSION: Our results highlighted molecular features of Turkish children with polycystic kidney disease and demonstrated novel variations that can be utilized in clinical diagnosis and prognosis.

Dominant Polycystic Kidney Disease with Acute Pyelonephritis due to Multi-drug Resistant Staphylococcus D Group and Candida albicans.

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary kidney disease caused due to a mutation in PKD1 gene and the PKD2 gene located at chromosome level 16 and chromosome 4. ADPKD often leads to progressive kidney (renal) failure, primarily due to continued enlargement of the cysts and replacement of normal kidney tissue. The present case is of a 70-year-old male diabetic patient with ADPKD along with acute pyelonephritis caused by multi-drug resistant Staphylococcus D group and Candida albicans, treated with a new antibiotic adjuvant entity ceftriaxone/sulbactam/disodium edetate, and fluconazole recovered completely.

Differential Expression of PKD2-Associated Genes in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by formation of multiple fluid-filled cysts that expand over time and destroy renal architecture. The proteins encoded by the PKD1 and PKD2 genes, mutations in which account for nearly all cases of ADPKD, may help guard against cystogenesis. Previously developed mouse models of PKD1 and PKD2 demonstrated an embryonic lethal phenotype and massive cyst formation in the kidney, indicating that PKD1 and PKD2 probably play important roles during normal renal tubular development. However, their precise role in development and the cellular mechanisms of cyst formation induced by PKD1 and PKD2 mutations are not fully understood. To address this question, we presently created Pkd2 knockout and PKD2 transgenic mouse embryo fibroblasts. We used a mouse oligonucleotide microarray to identify messenger RNAs whose expression was altered by the overexpression of the PKD2 or knockout of the Pkd2. The majority of identified mutations was involved in critical biological processes, such as metabolism, transcription, cell adhesion, cell cycle, and signal transduction. Herein, we confirmed differential expressions of several genes including aquaporin-1, according to different PKD2 expression levels in ADPKD mouse models, through microarray analysis. These data may be helpful in PKD2-related mechanisms of ADPKD pathogenesis.

Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a non-selective cation channel permeable to Ca2+, while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin (mTOR) and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials.

Expression Profiles of Mutant PKD2 Gene Overexpression in HEK 293 Cells / 대한신장학회잡지

BACKGROUND: PKD2 gene, encoding polycystin-2 protein is a cause of autosomal dominant polycystic kidney disease (ADPKD) forms cyst in the kidney, liver, and pancreas and result cardiac defects. Polycystin-2 protein interacts with polycystin-1 to produce calcium-permeable non-selective cation current but this signaling pathway was unknown well. To identify expression profiles of mutant PKD2 gene overexpressed HEK 293 cells and EF-hand motif function, we execute microarray experiment using mutant (m1, m1/m2) PKD2 overexpressed cells. METHODS: cDNA probes were prepared by labeling mRNA from mutant (m1, m1/m2) PKD2 overexpressed cells with Cy5-dUTP and Cy3-dUTP through reverse transcription. The mixed probes of each sample were then hybridized with 14, 080 cDNA microarray, and the fluorescent signals were scanned by Arraywox scanner (Applied Precision LLC. Northeastern, USA). The values of Cy5-dUTP and Cy3- dUTP on each spot were analyzed and calculated by ImaGene 5.1 software (BioDiscovery Inc., El Segundo, CA, USA). Normalization was performed by using subtract mean and all genes. RESULTS: It PKD2 over-expressed cells, up-regulated genes were 11 containing PTK2 and down-regulated genes were 27 including MAP2, ABS. In mutant (m1) PKD2 genes, up-regulated genes were 20 and down-regulated genes were 121. In mutant (m1/m2) PKD2 genes, up-regulated genes were 363 and down-regulated genes were 360, respectively. Based on the clustering data, up-regulated genes were 5 containing IL4R and SIL1, and down-regulated genes were 6 including SAE1 and CPSF4. CONCLUSION: Microarray analysis may provide invaluable information on the role of mutant PKD2 gene product. In this study, we have used a high-density cDNA microarray technique to assess the gene expression profile of mutant (m1, m1/m2) PKD2 overexpression cells. Value of up- and down-regulated genes normalized by Genesight 3.2 version software compared with M/A plot data to identify confidence of data. Selected genes numbers were different, but the level of fold value was similar. Finally, we identified that several genes maybe involve in PKD2 function.

Clinical and Genetic Characteristics of 49 Probands of Autosomal Dominant Polycystic Kidney Disease in Korea / 대한신장학회잡지

We analysed the 49 probands of autosomal dominant polycystic kidney disease (ADPKD) in Korea to elucidate clinical and genetic characteristics. 1) Family history of renal disease or ADPKD was taken from 44% of probands; hypertension 88%, cerebrovascular attack 64%, end stage renal disease 16%. 2) From the family screening with renal ultrasonography, we have confirmed dominant trait in 24 families. We found 2 families which have suspicious new mutations. 3) We performed linkage analysis of 15 families. The PKD-1 to non PKD-1 ratio was 13 : 2. 4) The male to femal ratio was 17 : 32 and age at diagnosis was 41 (24-65)years (mean (range)) in male, 45 (26-68) years in female. 5) The factors leading to the diagnosis of ADPKD were flank pain (23%), incidental finding (17%), palpable abdominal mass (11%), headache (9%) and gross hematuria (9%) 3) Hypertension (80%), azotemia (43%), flank pain (42%), renal calcification (42%), gross hematuria (33%) and cyst hemorrhage (25%) were renal complications. There were 2 renal cell carcinoma cases. 4)Liver cyst (82%) was the most common extrarenal manifestations. There were colonic diverticulosis (13%), cerebral artery aneurysm (7%), adrenal cyst (4%) and pancreatic cyst (2%). Results of our study revealed the clinical and genetic characteristics of ADPKD in Korea. We found only 44% of family history of renal disease, variable initial manifestations, variable renal and extrarenal complications. And we also found the similar percentage of PKD-2 (13%) to that (5-15%) of western countries, but it is necessary to study with more patients and families.