scholarly journals Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes

2021 ◽  
Vol 8 ◽  
Author(s):  
Chengxian Xu ◽  
Chenxi Yang ◽  
Qing Ye ◽  
Jie Xu ◽  
Lingxiao Tong ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
De Novo ◽  
Cell Junctions ◽  
Renal Tubules ◽  
Tubular Epithelial Cells ◽  
Polycystic Kidney ◽  
Renal Cystic Disease ◽  
Pathologic Features ◽  
Collecting Ducts ◽  
Lysosomal Proteins

Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease caused mainly by the polycystic kidney and hepatic disease 1 (PKHD1). However, the genetic cause, pathologic features, and mechanism of action of ARPKD are not well known. Here, we identified a family with ARPKD. Two siblings harbored biallelic variants in PKHD1 (c.7205G>A, c.7973T>A). We determined that the “de novo” variant, c.7205G>A, arose from the mosaicism of the father and had a 7.4% level. Pathologic characterization, using biopsy analysis, was evidenced with predominant cystic dilation in proximal tubules, slight ectasia of collecting ducts, defective ciliogenesis, and impaired cell-cell junctions in renal tubules and collecting ducts. Exosome proteomics in the urine from patients with ARPKD were markedly different from those of controls, with the most significant alterations occurring in mitochondrial and lysosomal proteins. Expression of the proteins of OXPHOS was downregulated sharply, in parallel with upregulated expression of the proteins involved in glycolysis in patients with ARPKD. Several lysosomal proteins associated with renal lesions were more abundant in the exosome of the patient than in controls. Moreover, the lysosomal enzyme sulfamidase, which is produced by the SGSH gene, was abrupt uniquely in the exosome of the patient. Consistently, swollen mitochondria and abundant lysosomes were visualized in the mutant tubular epithelial cells of patients with mutant PKHD1. Collectively, these findings provide new insights on the pathophysiology of the polycystic kidney due to PKHD1 deficiency. PKHD1 mosaicism should be considered in genetic testing of ARPKD patients.

Dichloroacetate treatment accelerates the development of pathology in rodent autosomal recessive polycystic kidney disease

2014 ◽  
Vol 307 (10) ◽  
pp. F1144-F1148 ◽  
Author(s):  
Vincent H. Gattone ◽  
Robert L. Bacallao
Keyword(s):  
Kidney Disease ◽  
Liver Function ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Renal Tubules ◽  
Liver Pathology ◽  
Sprague Dawley ◽  
Polycystic Kidney ◽  
Renal Cystic Disease ◽  
Increased Sensitivity

Dichloroacetate (DCA) is a toxicant by-product from the chlorination disinfection process for municipal water. The levels would not affect people with normal renal and liver function. However, people with impaired renal or liver function may have an increased susceptibility to DCA toxicity as those are the organs affected by DCA. People (and rodents) with polycystic kidney disease (PKD) are polyuric, drink more fluids, and have both renal and liver pathology. In PKD, renal tubules and biliary epithelial cells proliferate to form cysts, which can eventually cause renal and/or liver dysfunction. Therefore, PKD may be a predisposing condition with an increased sensitivity to DCA toxicity. PCK rats are an orthologous model of human autosomal recessive PKD and were treated with 75 mg/l DCA in their drinking water. Male and female PCK and male Sprague-Dawley rats were treated from 4 to 8 wk of age, after which the severity of the renal and liver pathology induced by DCA were assessed. Only male PCK rats were adversely affected by DCA treatment, with an increase in the severity of renal cystic disease evinced by an increase in cystic enlargement and proteinuria. In conclusion, the chlorination byproduct DCA may adversely affect those with a preexisting renal disease, especially those who are polydipsic, like those with PKD.

Congenital Cystic Disease of the Liver, Pancreas, and Kidney in a Nubian Goat (Capra hircus)

1996 ◽  
Vol 33 (6) ◽  
pp. 708-710 ◽  
Author(s):  
K. Krotec ◽  
B. Smith Meyer ◽  
W. Freeman ◽  
A. N. Hamir
Keyword(s):  
Bile Ducts ◽  
Autosomal Recessive ◽  
Animal Species ◽  
Capra Hircus ◽  
Cystic Disease ◽  
Polycystic Kidney ◽  
Hepatic Parenchyma ◽  
Collecting Ducts ◽  
Liver And Pancreas ◽  
Extrahepatic Bile Ducts

A congenital cystic disease of the liver, pancreas, and kidney was diagnosed in a 3-week-old female Nubian goat ( Capra hircus). Gross and histologic features were similar to autosomal recessive polycystic kidney disease in humans and to previous reports of juvenile polycystic disorders in several animal species. Grossly, the lesions were confined to the liver and pancreas. The liver was severely enlarged and contained multiple fluid-filled cysts of various sizes. There was tortuous ectasia of the extrahepatic bile ducts. In the pancreas, multiple small cysts were disseminated throughout the parenchyma. Histologically, there was cavernous ectasia of the intra- and extrahepatic biliary system. Dilated intrahepatic biliary channels formed a branching and anastomosing pattern throughout the hepatic parenchyma and were often bordered by fibrous connective tissue. The pancreas had dilation of intra- and interlobular ducts. Renal cortical tubules and collecting ducts were ectatic. Congenital polycystic disorder has not been documented previously in the goat.

scholarly journals New Rat Model that Phenotypically Resembles Autosomal Recessive Polycystic Kidney Disease

2000 ◽  
Vol 11 (12) ◽  
pp. 2272-2284
Author(s):  
JEROEN NAUTA ◽  
MIRIAM A. GOEDBLOED ◽  
HARRY VAN HERCK ◽  
DENNIS A. HESSELINK ◽  
PIM VISSER ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Experimental Model ◽  
Polycystic Kidney Disease ◽  
Rat Model ◽  
Autosomal Recessive ◽  
Molecular Pathogenesis ◽  
Polycystic Kidney ◽  
Specific Staining ◽  
Collecting Ducts ◽  
Histopathologic Features

Abstract. Numerous murine models of polycystic kidney disease (PKD) have been described. While mouse models are particularly well suited for investigating the molecular pathogenesis of PKD, rats are well established as an experimental model of renal physiologic processes. Han:SPRD-Cy rats have been proposed as a model for human autosomal dominant PKD. A new spontaneous rat mutation, designated wpk, has now been identified. In the mutants, the renal cystic phenotype resembles human autosomal recessive PKD (ARPKD). This study was designed to characterize the clinical and histopathologic features of wpk/wpk mutants and to map the wpk locus. Homozygous mutants developed nephromegaly, hypertension, proteinuria, impaired urine-concentrating capacity, and uremia, resulting in death at 4 wk of age. Early cysts were present in the nephrogenic zone at embryonic day 19. These were localized, by specific staining and electron microscopy, to differentiated proximal tubules, thick limbs, distal tubules, and collecting ducts. In later stages, the cysts were largely confined to collecting ducts. Although the renal histopathologic features are strikingly similar to those of human ARPKD, wpk/wpk mutants exhibited no evidence of biliary tract abnormalities. The wpk locus maps just proximal to the Cy locus on rat chromosome 5, and complementation studies demonstrated that these loci are not allelic. It is concluded that the clinical and renal histopathologic features of this new rat model strongly resemble those of human ARPKD. Although homology mapping indicates that rat wpk and human ARPKD involve distinct genes, this new rat mutation provides an excellent experimental model to study the molecular pathogenesis and renal pathophysiologic features of recessive PKD.

scholarly journals A hereditary model of slowly progressive polycystic kidney disease in the mouse.

1991 ◽  
Vol 1 (7) ◽  
pp. 980-989 ◽  
Author(s):  
H Takahashi ◽  
J P Calvet ◽  
D Dittemore-Hoover ◽  
K Yoshida ◽  
J J Grantham ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Coat Color ◽  
Collecting Duct ◽  
Basement Membranes ◽  
Chromosome 9 ◽  
Polycystic Kidney ◽  
Dominant Form ◽  
Renal Cystic Disease

There are two known forms of hereditary polycystic kidney disease (PKD) in humans. Although both forms initiate early in life, autosomal recessive PKD is rapidly progressive to kidney failure shortly after birth whereas autosomal dominant PKD is slowly progressive, taking many years to end stage. Research in this field has been limited by the availability of suitable animal models of PKD. Recently the C57BL/6J-cpk mouse has been used to study the pathogenesis of rapidly progressive hereditary PKD. The study presented here describes a slowly progressive PKD in the DBA/2-pcy mouse. The disease trait is transmitted in an autosomal recessive pattern and was localized to chromosome 9 through linkage to the dilute coat color and transferrin genes. Whereas some cystic changes were seen in fetal and newborn affected mice, renal enlargement did not develop until after 8 weeks of age and azotemia did not develop until after 18 weeks of age. Renal cysts were identified in all segments of the nephron and collecting duct and progressively enlarged with age. Individual cysts were found to be lined by a single layer of epithelial cells in most areas, with focal polyps and mounds of cells principally in collecting duct cysts. Early stages of cyst formation were associated with some abnormalities of tubular and glomerular basement membranes and accelerated eruption of incisors. Late stages of the disease were characterized by azotemia and chronic renal interstitial inflammatory infiltrates in all affected animals and cerebral vascular aneurysms in a few. We conclude that the DBA/2-pcy mouse has a form of renal cystic disease that appears similar in many respects to that seen in the dominant form of human PKD.

scholarly journals Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chaozhe Yang ◽  
Naoe Harafuji ◽  
Amber K. O’Connor ◽  
Robert A. Kesterson ◽  
Jacob A. Watts ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Fusion Protein ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Collecting Duct ◽  
Polycystic Kidney ◽  
Specific Expression ◽  
Human Patient ◽  
Renal Cystic Disease ◽  
Gfp Fusion Protein

AbstractMutation of the Cys1 gene underlies the renal cystic disease in the Cys1cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells down-regulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a deleterious splicing variant in CYS1. These findings suggest that mutations in Cys1/CYS1 cause an ARPKD phenotype in mouse and human, respectively, and that the renal cystic phenotype in the mouse is driven by overexpression of the Myc proto-oncogene.

scholarly journals Novel Mutation in thePKHD1Gene Diagnosed Prenatally in a Fetus with Autosomal Recessive Polycystic Kidney Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-6
Author(s):  
Pankaj Thakur ◽  
Paul Speer ◽  
Aleksandar Rajkovic
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
De Novo ◽  
Novel Mutation ◽  
Allelic Heterogeneity ◽  
Polycystic Kidney ◽  
Amniotic Fluid Index ◽  
Presumptive Diagnosis

We report a 29-year-old gravida 2, para 0100, who presented at 19 weeks and 4 days of gestation for ultrasound to assess fetal anatomy. Routine midtrimester fetal anatomy ultrasound revealed enlarged, hyperechoic fetal kidneys and normal amniotic fluid index. Follow-up ultrasound at 23 weeks and 5 days revealed persistently enlarged, hyperechoic fetal kidneys. Progressive oligohydramnios was not evident until 29 weeks of gestation, with anhydramnios noted by 35 weeks of gestation. Amniocentesis was performed for karyotype and to search for mutations in thePKHD1for the presumptive diagnosis of autosomal recessive polycystic kidney disease (ARPKD). In our patient, a maternally inherited, previously reported pathogenic missense mutation in thePKHD1gene, c.10444C>T, was identified. A second, previously unreportedde novomutation, c.5909-2delA, was also identified. This mutation affects the canonical splice site and is most likely pathogenic. Our case highlightsPKHD1allelic heterogeneity and the importance of genetic testing in the prenatal setting where many other genetic etiologies can phenocopy ARPKD.

Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented?

2001 ◽  
Vol 21 (5) ◽  
pp. 430-440 ◽  
Author(s):  
Ira D. Davis ◽  
Katherine MacRae Dell ◽  
William E. Sweeney ◽  
Ellis D. Avner
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Polycystic Kidney

scholarly journals Imaging manifestations of Caroli disease with autosomal recessive polycystic kidney disease: a case report and literature review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiuzhen Yao ◽  
Weiqun Ao ◽  
Jianhua Fang ◽  
Guoqun Mao ◽  
Chuanghua Chen ◽  
...  
Keyword(s):  
Pregnant Woman ◽  
Magnetic Resonance ◽  
Kidney Disease ◽  
Portal Vein ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Polycystic Kidney ◽  
Left Liver Lobe ◽  
Caroli Disease ◽  
T1 And T2

Abstract Background Both Caroli disease (CD) and autosomal recessive polycystic kidney disease (ARPKD) are autosomal recessive disorders, which are more commonly found in infants and children, for whom surviving to adulthood is rare. Early diagnosis and intervention can improve the survival rate to some extent. This study adopted the case of a 26-year-old pregnant woman to explore the clinical and imaging manifestations and progress of CD concomitant with ARPKD to enable a better understanding of the disease. Case presentation A 26-year-old pregnant woman was admitted to our hospital for more than 2 months following the discovery of pancytopenia and increased creatinine. Ultrasonography detected an enlarged left liver lobe, widened hepatic portal vein, splenomegaly, and dilated splenic vein. In addition, both kidneys were obviously enlarged and sonolucent areas of varying sizes were visible, but color Doppler flow imaging revealed no abnormal blood flow signals. The gestational age was approximately 25 weeks, which was consistent with the actual fetal age. Polyhydramnios was detected but no other abnormalities were identified. Magnetic resonance imaging revealed that the liver was plump, and polycystic liver disease was observed near the top of the diaphragm. The T1 and T2 weighted images were the low and high signals, respectively. The bile duct was slightly dilated; the portal vein was widened; and the spleen volume was enlarged. Moreover, the volume of both kidneys had increased to an abnormal shape, with multiple, long, roundish T1 and T2 abnormal signals being observed. Magnetic resonance cholangiopancreatography revealed that intrahepatic cystic lesions were connected with intrahepatic bile ducts. The patient underwent a genetic testing, the result showed she carried two heterozygous mutations in PKHD1. The patient was finally diagnosed with CD with concomitant ARPKD. The baby underwent a genetic test three months after birth, the result showed that the patient carried one heterozygous mutations in PKHD1, which indicated the baby was a PKHD1 carrier. Conclusions This case demonstrates that imaging examinations are of great significance for the diagnosis and evaluation of CD with concomitant ARPKD.

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