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Peter C Harris - One of the best experts on this subject based on the ideXlab platform.
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Autosomal Dominant Polycystic Kidney Patients May Be Predisposed to Various Cardiomyopathies
2017Co-Authors: Fouad T. Chebib, Marie C. Hogan, Ziad M. El-zoghby, Maria V. Irazabal, Sarah R. Senum, Christina M. Heyer, Charles D. Madsen, Emilie Cornec-le Gall, Atta Behfar, Peter C HarrisAbstract:Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). Experimental evidence suggests an important role of the polycystins in cardiac development and myocardial function. To determine whether ADPKD may predispose to the development of cardiomyopathy, we have evaluated the coexistence of diagnoses of ADPKD and primary cardiomyopathy in our patients. Methods: Clinical data were retrieved from medical records for patients with a coexisting diagnosis of ADPKD and cardiomyopathies evaluated at the Mayo Clinic (1984–2015). Results: Among the 58 of 667 patients with available echocardiography data, 39 (5.8%) had idiopathic dilated cardiomyopathy (IDCM), 17 (2.5%) had hypertrophic obstructive cardiomyopathy, and 2 (0.3%) had left ventricular noncompaction. Genetic data were available for 19, 8, and 2 cases of IDCM, hypertrophic obstructive cardiomyopathy, and left ventricular noncompaction, respectively. PKD1 mutations were detected in 42.1%, 62.5%, and 100% of IDCM, hypertrophic obstructive cardiomyopathy, and left ventricular noncompaction cases, respectively. PKD2 mutations were detected only in IDCM cases and were overrepresented (36.8%) relative to the expected frequency in ADPKD (15%). In at least 1 patient from 3 IDMC families and 1 patient from a hypertrophic obstructive cardiomyopathy family, the cardiomyopathy did not segregate with ADPKD, suggesting that the PKD mutations may be predisposing factors rather than solely responsible for the development of cardiomyopathy. Discussion: Coexistence of ADPKD and cardiomyopathy in our tertiary referral center cohort appears to be higher than expected by chance. We suggest that PKD1 and PKD2 mutations may predispose to primary cardiomyopathies and that genetic interactions may account for the observed coexistence of ADPKD and cardiomyopathies
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autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model
2016Co-Authors: Ping Zhu, Peter C Harris, Cynthia J Sieben, Xueying LinAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. It is one of the most common heritable human diseases with eventual development of renal failure; however, effective treatment is lacking. While inhibition of mechanistic target of rapamycin (mTOR) effectively slows cyst expansions in animal models, results from clinical studies are controversial, prompting further mechanistic studies of mTOR-based therapy. Here, we aim to establish autophagy, a downstream pathway of mTOR, as a new therapeutic target for PKD. We generated zebrafish mutants for PKD1 and noted cystic kidney and mTOR activation in PKD1a mutants, suggesting a conserved ADPKD model. Further assessment of the mutants revealed impaired autophagic flux, which was conserved in kidney epithelial cells derived from both PKD1-null mice and ADPKD patients. We found that inhibition of autophagy by knocking down the core autophagy protein Atg5 promotes cystogenesis, while activation of autophagy using a specific inducer Beclin-1 peptide ameliorates cysts in the PKD1a model. Treatment with compound autophagy activators, including mTOR-dependent rapamycin as well as mTOR-independent carbamazepine and minoxidil, markedly attenuated cyst formation and restored kidney function. Finally, we showed that combination treatment with low doses of rapamycin and carbamazepine was able to attenuate cyst formation as effectively as a single treatment with a high dose of rapamycin alone. In summary, our results suggested a modifying effect of autophagy on ADPKD, established autophagy activation as a novel therapy for ADPKD, and presented zebrafish as an efficient vertebrate model for developing PKD therapeutic strategies.
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effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease
2016Co-Authors: Fouad T. Chebib, Peter C Harris, Marie C. Hogan, Maria V. Irazabal, Christina M. Heyer, Vicente E Torres, Yeonsoon Jung, Ziad M ElzoghbyAbstract:The autosomal dominant polycystic kidney disease (APDKD) genotype influences renal phenotype severity but its effect on polycystic liver disease (PLD) is unknown. Here we analyzed the influence of genotype on liver phenotype severity.Clinical data were retrieved from electronic records of patients who were mutation screened with the available liver imaging (n = 434). Liver volumes were measured by stereology (axial or coronal images) and adjusted to height (HtLV).Among the patients included, 221 (50.9%) had truncating PKD1 (PKD1-T), 141 (32.5%) nontruncating PKD1 (PKD1-NT) and 72 (16.6%) PKD2 mutations. Compared with PKD1-NT and PKD2, patients with PKD1-T had greater height-adjusted total kidney volumes (799 versus 610 and 549 mL/m; P < 0.001). HtLV was not different (1042, 1095 and 1058 mL/m; P = 0.64) between the three groups, but females had greater HtLVs compared with males (1114 versus 1015 mL/m; P < 0.001). Annualized median liver growth rates were 1.68, 1.5 and 1.24% for PKD1-T, PKD1-NT and PKD2 mutations, respectively (P = 0.49), and remained unaffected by the ADPKD genotype when adjusted for age, gender and baseline HtLV. Females <48 years of age had higher annualized growth rates compared with those who were older (2.65 versus 0.09%; P < 0.001). After age 48 years, 58% of females with severe PLD had regression of HtLV, while HtLV continued to increase in males.In contrast to the renal phenotype, the ADPKD genotype was not associated with the severity or growth rate of PLD in ADKPD patients. This finding, along with gender influence, indicates that modifiers beyond the disease gene significantly influence the liver phenotype.
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Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated.
2015Co-Authors: Cristina Cabrera-lópez, Peter C Harris, Gemma Bullich, Jose Ballarin, Teresa Sordé Martí, Violeta Catalá, John J. Bissler, Roser TorraAbstract:Background: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), while mutations in PKD1 or PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). PKD1 lays immediately adjacent to TSC2 and deletions involving both genes, the PKD1/TSC2 contiguous gene syndrome (CGS), are characterized by severe ADPKD, plus TSC. mTOR inhibitors have proven effective in reducing angiomyolipoma (AML) in TSC and total kidney volume in ADPKD but without a positive effect on renal function. Methods and results: We describe a patient with independent truncating PKD1 and TSC2 mutations who has the expected phenotype for both diseases independently instead of the severe one described in PKD1/TSC2-CGS. Treatment with mTOR inhibitors reduced the AML and kidney volume for 2 years but thereafter they resumed growth; no positive effect on renal function was seen thro ughout. This is the first case addressing the response to mTOR treatment when independent truncating mutations in PKD1 and TSC2 are present. Conclusions: This case reveals that although PKD1 and TSC2 are adjacent genes and there is likely cross-talk between the PKD1 and TSC2 signalling pathways regulating mTOR, having independent TSC2 and PKD1 mutations can give rise to a milder kidney phenotype than is typical in PKD1/TSC2-CGS cases. A short-term beneficial effect of mTOR inhibition on AML and total kidney volume was not reflected in improved renal function.
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polycystin 1 maturation requires polycystin 2 in a dose dependent manner
2015Co-Authors: Vladimir G Gainullin, Christopher J. Ward, Katharina Hopp, Cynthia J Hommerding, Peter C HarrisAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited nephropathy responsible for 4%–10% of end-stage renal disease cases. Mutations in the genes encoding polycystin-1 (PC1, PKD1) or polycystin-2 (PC2, PKD2) cause ADPKD, and PKD1 mutations are associated with more severe renal disease. PC1 has been shown to form a complex with PC2, and the severity of PKD1-mediated disease is associated with the level of the mature PC1 glycoform. Here, we demonstrated that PC1 and PC2 first interact in the ER before PC1 cleavage at the GPS/GAIN site and determined that PC2 acts as an essential chaperone for PC1 maturation and surface localization. The chaperone function of PC2 was dependent on the presence of the distal coiled-coil domain and was disrupted by pathogenic missense mutations. In Pkd2–/– mice, complete loss of PC2 prevented PC1 maturation. In Pkd2 heterozygotes, the 50% PC2 reduction resulted in a nonequimolar reduction (20%–25%) of the mature PC1 glycoform. Interbreeding between various PKD1 and Pkd2 models revealed that animals with reduced levels of functional PC1 and PC2 in the kidney exhibited severe, rapidly progressive disease, illustrating the importance of complexing of these proteins for function. Our results indicate that PC2 regulates PC1 maturation; therefore, mature PC1 levels are a determinant of disease severity in PKD2 as well as PKD1.
Gregory G Germino - One of the best experts on this subject based on the ideXlab platform.
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network analysis of a PKD1 mouse model of autosomal dominant polycystic kidney disease identifies hnf4α as a disease modifier
2012Co-Authors: Luis F Menezes, Klaus Piontek, Fang Zhou, Andrew D Patterson, Kristopher W Krausz, Frank J Gonzalez, Gregory G GerminoAbstract:Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID's 173900, 601313, 613095) leads to end-stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of PKD1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed PKD1 alleles and an inducible Cre recombinase, we intensively analyzed the relationship between renal maturation and cyst formation by applying transcriptomics and metabolomics to follow disease progression in a large number of animals induced before P10. Weighted gene co-expression network analysis suggests that PKD1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. Knowledge-based Ingenuity Pathway Analysis (IPA) software identifies HNF4α as a likely network node. These results are further supported by a meta-analysis of 1,114 published gene expression arrays in PKD1 wild-type tissues. These analyses also predict that metabolic pathways are key elements in postnatal kidney maturation and early steps of cyst formation. Consistent with these findings, urinary metabolomic studies show that PKD1 cystic mutants have a distinct profile of excreted metabolites, with pathway analysis suggesting altered activity in several metabolic pathways. To evaluate their role in disease, metabolic networks were perturbed by inactivating Hnf4α and PKD1. The PKD1/Hnf4α double mutants have significantly more cystic kidneys, thus indicating that metabolic pathways could play a role in PKD1-cystogenesis.
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a missense mutation in PKD1 attenuates the severity of renal disease
2012Co-Authors: York Pei, Kairong Wang, Patrick S. Parfrey, Miguel A Garciagonzalez, Gregory G Germino, Zheng Lan, Elizabeth Dicks, Terry WatnickAbstract:Mutations of PKD1 and PKD2 account for most cases of autosomal dominant polycystic kidney disease (ADPKD). Compared with PKD2, patients with PKD1 typically have more severe renal disease. Here, we report a follow-up study of a unique multigeneration family with bilineal ADPKD (NFL10) in which a PKD1 disease haplotype and a PKD2 (L736X) mutation co-segregated with 18 and 14 affected individuals, respectively. In our updated genotype–phenotype analysis of the family, we found that PKD1-affected individuals had uniformly mild renal disease similar to the PKD2-affected individuals. By sequencing all the exons and splice junctions of PKD1 , we identified two missense mutations (Y528C and R1942H) from a PKD1-affected individual. Although both variants were predicted to be damaging to the mutant protein, only Y528C co-segregated with all of the PKD1-affected individuals in NFL10. Studies in MDCK cells stably expressing wild-type and mutant forms of PKD found that cell lines expressing the Y528C variant formed cysts in culture and displayed increased rates of growth and apoptosis. Thus, Y528C functions as a hypomorphic PKD1 allele. These findings have important implications for pathogenic mechanisms and molecular diagnostics of ADPKD.
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PKD1 and pkd2 are required for normal placental development
2010Co-Authors: Miguel A Garciagonzalez, Klaus Piontek, Gregory G Germino, Patricia Outeda, Qin Zhou, Fang Zhou, Luis F Menezes, Feng Qian, David L Huso, Terry WatnickAbstract:Background Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of inherited renal failure that results from mutations in PKD1 and PKD2. The disorder is characterized by focal cyst formation that involves somatic mutation of the wild type allele in a large fraction of cysts. Consistent with a two-hit mechanism, mice that are homozygous for inactivating mutations of either PKD1 or Pkd2 develop cystic kidneys, edema and hemorrhage and typically die in midgestation. Cystic kidney disease is unlikely to be the cause of fetal loss since renal function is not required to complete gestation. One hypothesis is that embryonic demise is due to leaky vessels or cardiac pathology. Methodology/Principal Findings In these studies we used a series of genetically modified PKD1 and Pkd2 murine models to investigate the cause of embryonic lethality in mutant embryos. Since placental defects are a frequent cause of fetal loss, we conducted histopathologic analyses of placentas from PKD1 null mice and detected abnormalities of the labyrinth layer beginning at E12.5. We performed placental rescue experiments using tetraploid aggregation and conditional inactivation of PKD1 with the Meox2 Cre recombinase. We found that both strategies improved the viability of PKD1 null embryos. Selective inactivation of PKD1 and Pkd2 in endothelial cells resulted in polyhydramnios and abnormalities similar to those observed in PKD1−/− placentas. However, endothelial cell specific deletion of PKD1 or Pkd2 did not yield the dramatic vascular phenotypes observed in null animals. Conclusions/Significance Placental abnormalities contribute to the fetal demise of Pkd−/− embryos. Endothelial cell specific deletion of PKD1 or Pkd2 recapitulates a subset of findings seen in Pkd null animals. Our studies reveal a complex role for polycystins in maintaining vascular integrity.
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loss of polycystin 1 or polycystin 2 results in dysregulated apolipoprotein expression in murine tissues via alterations in nuclear hormone receptors
2006Co-Authors: Erica Allen, Klaus Piontek, Elizabeth Garrettmayer, Miguel A Garciagonzalez, Kerry Lee Gorelick, Gregory G GerminoAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of PKD1 and PKD2. Murine gene targeting studies have shown that these genes play an essential role in development, with homozygous inactivation resulting in embryonic lethality. Recently, PKD1 -/- lethality has been linked to placental insufficiency. In this study, the placenta was used as a model to identify factors involved in these developmental abnormalities. Microarray analysis of PKD1 -/- placentae showed upregulation of a set of apolipoprotein-related genes. These changes were validated and were found to be associated with increased quantities of apolipoproteins in the amniotic fluid. Increased apolipoprotein gene expression was also observed in Pkd2 -/- placentae and in cystic kidneys of PKD1 cond/- ; Meox2 cre/+ mice. Using chromatin immunoprecipitation assays, we determined that the activity of HNF-4a, a major regulator of apolipoprotein gene expression, was also increased in these organs. These findings suggest a potential role for dysregulation of nuclear hormone receptors in the pathogenesis of ADPKD.
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expression of PKD1 and pkd2 transcripts and proteins in human embryo and during normal kidney development
2002Co-Authors: Veronique Chauvet, Olivier Devuyst, Feng Qian, Nicolas Boute, Yiqiang Cai, Bunyong Phakdeekitacharoen, Luis F Onuchic, Tania Attiebitach, Liliane Guicharnaud, Gregory G GerminoAbstract:Autosomal-dominant polycystic kidney disease, one of the most frequent human genetic disorders, is genetically heterogeneous. Most cases result from mutations of PKD1 or PKD2 encoding polycystin-1 or polycystin-2, respectively. Polycystin-1 is a large transmembrane protein containing several domains involved in cell-cell and/or cell-matrix interactions. Polycystin-2 is transmembrane glycoprotein sharing homology with some families of cation channels. Despite a large number of reports, the tissue distribution of these two proteins, especially of polycystin-1, is still debated. We investigated the expression pattern of PKD1 and PKD2 transcripts and proteins during human embryogenesis and kidney development, using Northern blot analysis, in situ hybridization, and immunohistochemical methods. For each gene, the expression pattern of transcripts and protein was concordant. In human 5- to 6-week-old embryos, both genes are widely expressed, mainly in neural tissue, cardiomyocytes, endodermal derivatives, and mesonephros. At this age, PKD2 but not PKD1 expression is observed in the ureteric bud and the uninduced metanephros. Thereafter, PKD2 is diffusely expressed at all stages of nephron development, whereas high PKD1 expression first appears in differentiated proximal tubules. Proximal tubule expression of both genes decreases from weeks 20 to 24 onwards. PKD1 transcripts, later restricted to distal tubules in fetal nephrogenesis, are no longer detected in adult kidneys, which nevertheless maintain a faint expression of polycystin-1, whereas persistent expression of PKD2 transcripts and protein is observed throughout nephrogenesis. Overall, contrary to previous observations, we found profound differences in the spatiotemporal expression of PKD1 and PKD2 during nephrogenesis, PKD2 being expressed earlier and more diffusely than PKD1. These data suggest that polycystins could interact with different partners, at least during kidney development.
Vicente E Torres - One of the best experts on this subject based on the ideXlab platform.
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effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease
2016Co-Authors: Fouad T. Chebib, Peter C Harris, Marie C. Hogan, Maria V. Irazabal, Christina M. Heyer, Vicente E Torres, Yeonsoon Jung, Ziad M ElzoghbyAbstract:The autosomal dominant polycystic kidney disease (APDKD) genotype influences renal phenotype severity but its effect on polycystic liver disease (PLD) is unknown. Here we analyzed the influence of genotype on liver phenotype severity.Clinical data were retrieved from electronic records of patients who were mutation screened with the available liver imaging (n = 434). Liver volumes were measured by stereology (axial or coronal images) and adjusted to height (HtLV).Among the patients included, 221 (50.9%) had truncating PKD1 (PKD1-T), 141 (32.5%) nontruncating PKD1 (PKD1-NT) and 72 (16.6%) PKD2 mutations. Compared with PKD1-NT and PKD2, patients with PKD1-T had greater height-adjusted total kidney volumes (799 versus 610 and 549 mL/m; P < 0.001). HtLV was not different (1042, 1095 and 1058 mL/m; P = 0.64) between the three groups, but females had greater HtLVs compared with males (1114 versus 1015 mL/m; P < 0.001). Annualized median liver growth rates were 1.68, 1.5 and 1.24% for PKD1-T, PKD1-NT and PKD2 mutations, respectively (P = 0.49), and remained unaffected by the ADPKD genotype when adjusted for age, gender and baseline HtLV. Females <48 years of age had higher annualized growth rates compared with those who were older (2.65 versus 0.09%; P < 0.001). After age 48 years, 58% of females with severe PLD had regression of HtLV, while HtLV continued to increase in males.In contrast to the renal phenotype, the ADPKD genotype was not associated with the severity or growth rate of PLD in ADKPD patients. This finding, along with gender influence, indicates that modifiers beyond the disease gene significantly influence the liver phenotype.
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predicted mutation strength of nontruncating PKD1 mutations aids genotype phenotype correlations in autosomal dominant polycystic kidney disease
2016Co-Authors: Christina M. Heyer, Jamie L Sundsbak, Kaleab Z Abebe, Arlene B Chapman, Vicente E Torres, Jared J Grantham, Kyongtae T Bae, Robert W Schrier, Ronald D Perrone, William E BraunAbstract:Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.
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functional polycystin 1 dosage governs autosomal dominant polycystic kidney disease severity
2012Co-Authors: Katharina Hopp, Christopher J. Ward, Vladimir G Gainullin, Cynthia J Hommerding, Vicente E Torres, Sandro Rossetti, Samih H Nasr, Han Fang Tuan, Peter C HarrisAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While PKD1+/null mice are normal, PKD1RC/null mice have rapidly progressive disease, and PKD1RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero–onset and typical ADPKD, respectively, correlating the level of functional PKD1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.
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identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing
2012Co-Authors: Sandro Rossetti, Christopher J. Ward, Katharina Hopp, Jamie L Sundsbak, Vicente E Torres, Vickie Kubly, Robert A Sikkink, Bruce W Eckloff, Christopher G Winearls, Peter C HarrisAbstract:Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1–32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing barcoded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from alleledropout,andwecharacterizedthepatternofdeepintronicvariationforbothgenes.Insummary,this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations.
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incompletely penetrant PKD1 alleles mimic the renal manifestations of arpkd
2010Co-Authors: Mihailo Vujic, Christina M. Heyer, Katharina Hopp, Elisabet Ars, Vicente E Torres, Arseni Markoff, Charlotte Orndal, Bengt Rudenhed, Samih H Nasr, Roser TorraAbstract:Autosomal dominant polycystic kidney disease (ADPKD), caused by mutation in PKD1 or PKD2, is usually an adult-onset disorder but can rarely manifest as a neonatal disease within a family characterized by otherwise typical ADPKD. Coinheritance of a hypomorphic PKD1 allele in trans with an inactivating PKD1 allele is one mechanism that can cause early onset ADPKD. Here, we describe two pedigrees without a history of cystic kidney disease that each contain two patients with onset of massive PKD in utero. The presentations were typical of autosomal recessive PKD (ARPKD) but they were not linked to the known ARPKD gene, PKHD1. Mutation analysis of the ADPKD genes provided strong evidence that both families inherited, in trans, two incompletely penetrant PKD1 alleles. These patients illustrate that PKD1 mutations can manifest as a phenocopy of ARPKD with respect to renal involvement and highlight the perils of linkage-based diagnostics in ARPKD without positive PKHD1 mutation data. Furthermore, the phenotypic overlap between ARPKD and these patients resulting from incomplete penetrant PKD1 alleles support a common pathogenesis for these diseases.
Dorien J M Peters - One of the best experts on this subject based on the ideXlab platform.
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comparative transcriptomics of shear stress treated PKD1 cells and pre cystic kidneys reveals pathways involved in early polycystic kidney disease
2018Co-Authors: Steven J Kunnen, Wouter N Leonhard, Tareq B Malas, Chiara Formica, Peter A C T Hoen, Dorien J M PetersAbstract:Mutations in the PKD1 or PKD2 genes are the cause of autosomal dominant polycystic kidney disease (ADPKD). The encoded proteins localize within the cell membrane and primary cilia and are proposed to be involved in mechanotransduction. Therefore, we evaluate shear stress dependent signaling in renal epithelial cells and the relevance for ADPKD. Using RNA sequencing and pathway analysis, we compared gene expression of in vitro shear stress treated PKD1-/- renal epithelial cells and in vivo pre-cystic PKD1del models. We show that shear stress alters the same signaling pathways in PKD1-/- renal epithelial cells and PKD1wt controls. However, expression of a number of genes was slightly more induced by shear stress in PKD1-/- cells, suggesting that PKD1 has the function to restrain shear regulated signaling instead of being a mechano-sensing activator. We also compared altered gene expression in PKD1-/- cells during shear with in vivo transcriptome data of kidneys from PKD1del mice at three early pre-cystic time-points. This revealed overlap of a limited number of differentially expressed genes. However, the overlap between cells and mice is much higher when looking at pathways and molecular processes, largely due to altered expression of paralogous genes. Several of the altered pathways in the in vitro and in vivo PKD1del models are known to be implicated in ADPKD pathways, including PI3K-AKT, MAPK, Hippo, calcium, Wnt, and TGF-β signaling. We hypothesize that increased activation of selected genes in renal epithelial cells early upon PKD1 gene disruption may disturb the balance in signaling and may contribute to cyst formation.
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neonatal onset autosomal dominant polycystic kidney disease adpkd in a patient homozygous for a pkd2 missense mutation due to uniparental disomy
2012Co-Authors: Monique Losekoot, Claudia A L Ruivenkamp, A P Tholens, J E M A Grimbergen, L Vijfhuizen, Sascha Vermeer, Henry B P M Dijkman, Elisabeth A M Cornelissen, Ernie M H F Bongers, Dorien J M PetersAbstract:Autosomal dominant polycystic kidney disease (ADPKD), due to a heterozygous mutation in PKD1 or PKD2, is usually an adult onset disease. Renal cystic disease is generally milder in PKD2 patients than in PKD1 patients. Recently, several PKD1 patients with a severe renal cystic phenotype due to a second modifying PKD1 allele, or carrying two incomplete penetrant PKD1 alleles, have been described. This study reports for the first time a patient with neonatal onset of PKD homozygous for an incomplete penetrant PKD2 missense variant due to uniparental disomy.
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curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways in vivo evidence from a PKD1 deletion model
2011Co-Authors: Wouter N Leonhard, Martijn H Breuning, Annemieke Van Der Wal, Zlata Novalic, Steven J Kunnen, Ron T Gansevoort, Emile De Heer, Dorien J M PetersAbstract:Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in either the PKD1 or PKD2 gene is a major cause of end-stage renal failure. A number of compounds targeting specific signal...
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genes homologous to the autosomal dominant polycystic kidney disease genes PKD1 and pkd2
1999Co-Authors: Barbera Veldhuisen, Lia Spruit, Hans G Dauwerse, Martijn H Breuning, Dorien J M PetersAbstract:Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common inherited disease leading to progressive renal failure, can be caused by a mutation in either the PKD1 or PKD2 gene. Both genes encode for putative transmembrane proteins, polycystin-1 and polycystin-2, which show significant homology to each other and are believed to interact at their carboxy termini. To identify genes that code for related proteins we searched for homologous sequences in several databases and identified one partial cDNA and two genomic sequences with significant homology to both polycystin-1 and - 2. Further analysis revealed one novel gene, PKD2L2, located on chromosome band 5q31, and two recently described genes, PKD2L and PKDREJ, located on chromosome bands 10q31 and 22q13.3, respectively. PKD2L2 and PKD2L, which encode proteins of 613 and 805 amino acids, are approximately 65% similar to polycystin-2. The third gene, PKDREJ, encodes a putative 2253 amino acid protein and shows about 35% similarity to both polycystin-1 and polycystin-2. For all the genes expression was found in testis. Additional expression of PKD2L was observed in retina, brain, liver and spleen by RT-PCR. Analyses of five ADPKD families without clear linkage to either the PKD1 or PKD2 locus showed no linkage to any of the novel loci, excluding these genes as the cause of ADPKD in these families. Although these genes may not be involved in renal cystic diseases, their striking homology to PKD2 and PKD1 implies similar roles and may contribute to elucidating the function of both polycystin-1 and polycystin-2.
Sandro Rossetti - One of the best experts on this subject based on the ideXlab platform.
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functional polycystin 1 dosage governs autosomal dominant polycystic kidney disease severity
2012Co-Authors: Katharina Hopp, Christopher J. Ward, Vladimir G Gainullin, Cynthia J Hommerding, Vicente E Torres, Sandro Rossetti, Samih H Nasr, Han Fang Tuan, Peter C HarrisAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While PKD1+/null mice are normal, PKD1RC/null mice have rapidly progressive disease, and PKD1RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero–onset and typical ADPKD, respectively, correlating the level of functional PKD1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.
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identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing
2012Co-Authors: Sandro Rossetti, Christopher J. Ward, Katharina Hopp, Jamie L Sundsbak, Vicente E Torres, Vickie Kubly, Robert A Sikkink, Bruce W Eckloff, Christopher G Winearls, Peter C HarrisAbstract:Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1–32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing barcoded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from alleledropout,andwecharacterizedthepatternofdeepintronicvariationforbothgenes.Insummary,this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations.
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incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease
2009Co-Authors: Sandro Rossetti, Katharina Hopp, Dominique Chauveau, Vickie Kubly, Mark B Consugar, Sushmita Roy, Sharon W Horsley, Lesley Rees, Martin T Barratt, William Vant HoffAbstract:Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed end stage renal disease at ages 75 and 62 years, while six heterozygotes had few cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small cysts of relatively uniform size while marked cyst heterogeneity is typical of ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional PKD1 protein may be critical for cyst initiation.
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characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1 tsc2 contiguous gene syndrome
2008Co-Authors: Mark B Consugar, Sandro Rossetti, Vickie Kubly, Wai C Wong, Patrick A Lundquist, Denise L Walker, Laureano J Rangel, Richard Aspinwall, Patrick W Niaudet, Seza OzenAbstract:Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.
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co inheritance of a PKD1 mutation and homozygous pkd2 variant a potential modifier in autosomal dominant polycystic kidney disease
2008Co-Authors: George Dedoussis, Sandro Rossetti, Ying Luo, Patrick G Starremans, Arnolt J Ramos, Horacio F Cantiello, E Katsareli, P Ziroyannis, Klea Lamnissou, Peter C HarrisAbstract:Background Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. Materials and methods We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. Results We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21–2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband’s parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient’s peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. Conclusions We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.