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

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 predicted deleterious splicing defect in CYS1. These findings suggest that mutations in the Cys1 mouse and CYS1 human orthologues cause an ARPKD phenotype that is driven by overexpression of the Myc proto-oncogene.Translational StatementThe cystin-deficient cpk mouse is a model for the study of autosomal recessive polycystic kidney disease (ARPKD). We show that the cpk mouse phenotype is associated with altered Myc expression. To date, the clinical relevance of cystin deficiency to human disease was unclear, due to the absence of ARPKD cases associated with CYS1 mutations. We report the first case of ARPKD linked to a CYS1 mutation disrupting normal splicing. These findings confirm the relevance of cystin deficiency to human ARPKD, implicate Myc in disease initiation or progression, and validate the cpk mouse as a translationally relevant disease model.

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

Journal of the American Society of Nephrology ◽

10.1681/asn.v17980 ◽

1991 ◽

Vol 1 (7) ◽

pp. 980-989 ◽

Cited By ~ 2

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.

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Altered bicarbonate‐dependent intracellular pH (pH i ) regulation in a cortical collecting duct (CCD) principal cell line from a mouse model of autosomal recessive polycystic kidney disease (ARPKD)

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.1024.10 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Xiaofen Liu ◽

Lauren A. Stephens ◽

Dragos Olteanu ◽

Mark O. Bevensee

Keyword(s):

Kidney Disease ◽

Mouse Model ◽

Cell Line ◽

Polycystic Kidney Disease ◽

Intracellular Ph ◽

Autosomal Recessive ◽

Collecting Duct ◽

Principal Cell ◽

Cortical Collecting Duct ◽

Polycystic Kidney

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The isolated polycystin-1 cytoplasmic COOH terminus prolongs ATP-stimulated Cl– conductance through increased Ca2+ entry

AJP Renal Physiology ◽

10.1152/ajprenal.00171.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. F1168-F1178 ◽

Cited By ~ 28

Author(s):

Scott S. Wildman ◽

Kimberly M. Hooper ◽

Clare M. Turner ◽

James S. K. Sham ◽

Edward G. Lakatta ◽

...

Keyword(s):

Kidney Disease ◽

Fusion Protein ◽

Polycystic Kidney Disease ◽

Collecting Duct ◽

Control Cell ◽

Fluid Secretion ◽

Cortical Collecting Duct ◽

Polycystic Kidney ◽

Pkd1 Gene ◽

Autosomal Dominant Polycystic Kidney

The precise steps leading from mutation of the polycystic kidney disease ( PKD1) gene to the autosomal dominant polycystic kidney disease (ADPKD) phenotype remain to be established. Fluid accumulation is a requirement for cyst expansion in ADPKD, suggesting that abnormal fluid secretion into the cyst lumen might play a role in disease. In this study, we sought to establish a link between polycystin-1 (the PKD1 gene product) and ATP-stimulated Cl– secretion in renal tubule cells. To do this, we performed a whole cell patch-clamp analysis of the effects of expression of the isolated cytoplasmic COOH-terminus of polycystin-1 in stably transfected mouse cortical collecting duct cells. The truncated polycystin-1 fusion protein prolonged the duration of ATP-stimulated Cl– conductance and intracellular Ca2+ responses. Both effects were dependent on extracellular Ca2+. It was determined that expression of the truncated polycystin-1 fusion protein introduced, or activated, an ATP-induced Ca2+ entry pathway that was undetectable in transfection control cell lines. Our findings are concordant with increasing evidence for a role of polycystin-1 in cell Ca2+ homeostasis and indicate that dysregulated Ca2+ entry might promote Cl– secretion and cyst expansion in ADPKD.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00009.2014 ◽

2014 ◽

Vol 307 (10) ◽

pp. F1144-F1148 ◽

Cited By ~ 3

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.

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Segment-Specific c-ErbB2 Expression in Human Autosomal Recessive Polycystic Kidney Disease

Journal of the American Society of Nephrology ◽

10.1681/asn.v122379 ◽

2001 ◽

Vol 12 (2) ◽

pp. 379-384

Author(s):

KOICHI NAKANISHI ◽

WILLIAM E. SWEENEY ◽

ELLIS D. AVNER

Keyword(s):

Kidney Disease ◽

Epithelial Cells ◽

Polycystic Kidney Disease ◽

Gestational Age ◽

Autosomal Recessive ◽

Growth Factor Receptor ◽

Polycystic Kidney ◽

Specific Expression ◽

Erbb2 Expression ◽

Egfr Expression

Abstract. c-ErbB2 (also referred to as Neu or HER2), a transmembrane glycoprotein with intrinsic tyrosine kinase activity, is structurally related to epidermal growth factor receptor (EGFR) and forms active heterodimers with EGFR as well as other members of the EGFR family. c-ErbB2 is reported to mediate differentiation and proliferation in epithelial cells and is expressed in a tissue-specific and developmental stage-specific manner. Given the role of EGFR in cystic renal epithelial hyperplasia and the immature phenotype of cystic renal epithelial cells, the segment-specific expression pattern of c-ErbB2 in human autosomal recessive polycystic kidney disease (ARPKD) was examined in nine ARPKD kidney specimens ranging from gestational age 17 wk through postnatal age 4 wk. c-ErbB2 staining of human ARPKD samples showed increased expression with increasing gestational age compared with normal human fetal and postnatal kidneys. This increased c-ErbB2 expression was primarily localized to the apical surfaces of cystic collecting tubule cells, similar to the pattern of EGFR expression, and paralleled collecting tubular cyst formation and growth.

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

Seminars in Nephrology ◽

10.1053/snep.2001.24937 ◽

2001 ◽

Vol 21 (5) ◽

pp. 430-440 ◽

Cited By ~ 23

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

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Faculty Opinions recommendation of Renin-angiotensin system activation in congenital hepatic fibrosis in the PCK rat model of autosomal recessive polycystic kidney disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3868956.3606054 ◽

2010 ◽

Author(s):

Maureen Jonas ◽

Rima Fawaz

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Hepatic Fibrosis ◽

Rat Model ◽

Autosomal Recessive ◽

Renin Angiotensin System ◽

Congenital Hepatic Fibrosis ◽

Polycystic Kidney ◽

Angiotensin System ◽

System Activation

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Gender-Dependent Phenotype in Polycystic Kidney Disease Is Determined by Differential Intracellular Ca2+ Signals

International Journal of Molecular Sciences ◽

10.3390/ijms22116019 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6019

Author(s):

Khaoula Talbi ◽

Inês Cabrita ◽

Rainer Schreiber ◽

Karl Kunzelmann

Keyword(s):

Cell Proliferation ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Collecting Duct ◽

Primary Cells ◽

Loss Of Function ◽

Polycystic Kidney ◽

Chloride Currents ◽

Duct Cells ◽

Collecting Duct Cells

Autosomal dominant polycystic kidney disease (ADPKD) is caused by loss of function of PKD1 (polycystin 1) or PKD2 (polycystin 2). The Ca2+-activated Cl− channel TMEM16A has a central role in ADPKD. Expression and function of TMEM16A is upregulated in ADPKD which causes enhanced intracellular Ca2+ signaling, cell proliferation, and ion secretion. We analyzed kidneys from Pkd1 knockout mice and found a more pronounced phenotype in males compared to females, despite similar levels of expression for renal tubular TMEM16A. Cell proliferation, which is known to be enhanced with loss of Pkd1−/−, was larger in male when compared to female Pkd1−/− cells. This was paralleled by higher basal intracellular Ca2+ concentrations in primary renal epithelial cells isolated from Pkd1−/− males. The results suggest enhanced intracellular Ca2+ levels contributing to augmented cell proliferation and cyst development in male kidneys. Enhanced resting Ca2+ also caused larger basal chloride currents in male primary cells, as detected in patch clamp recordings. Incubation of mouse primary cells, mCCDcl1 collecting duct cells or M1 collecting duct cells with dihydrotestosterone (DHT) enhanced basal Ca2+ levels and increased basal and ATP-stimulated TMEM16A chloride currents. Taken together, the more severe cystic phenotype in males is likely to be caused by enhanced cell proliferation, possibly due to enhanced basal and ATP-induced intracellular Ca2+ levels, leading to enhanced TMEM16A currents. Augmented Ca2+ signaling is possibly due to enhanced expression of Ca2+ transporting/regulating proteins.

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

BMC Pregnancy and Childbirth ◽

10.1186/s12884-021-03768-8 ◽

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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