2008 Homer W. Smith Award: Insights into the Pathogenesis of Polycystic Kidney Disease from Gene Discovery : Journal of the American Society of Nephrology

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2008 Homer W. Smith Award

Insights into the Pathogenesis of Polycystic Kidney Disease from Gene Discovery

Harris, Peter C.

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Journal of the American Society of Nephrology 20(6):p 1188-1198, June 2009. | DOI: 10.1681/ASN.2009010014
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The twists and turns of a research career and the ultimate direction it takes often resemble happenstance rather than a carefully choreographed life plan. In my case, chance factors resulted in a quarter-century musing about renal cystic diseases. My undergraduate training in genetics at the University of East Anglia (Norwich, England) and PhD in medical genetics under the tutorage of Malcolm Ferguson-Smith at the University of Glasgow (Glasgow, Scotland) certainly piqued my interests in Mendelian disorders. My interests were heightened by the era; this was the time when positional cloning (it was called reverse genetics back then) was just starting to show promise to identify the primary defect in common monogenic disorders. As well as temporal considerations, spatial factors were a strong influence. My first postdoctoral position with Sam Latt at Children's Hospital, Boston, was just down the hall from where Lou Kunkel and Tony Monaco were identifying the Duchenne muscular dystrophy gene and a couple of floors below where Stu Orkin was identifying the chronic granulomatous disease gene, the first successes of positional cloning.1,2

In 1985, I first became aware of polycystic kidney disease (PKD), specifically autosomal dominant PKD (ADPKD; adult PKD as it was known then), when Steve Reeders visited Children's Hospital and presented his work from Oxford (later published in Nature3) of linkage of an ADPKD gene to chromosome 16, just 5 cM from the α-globin locus. So started a project, initially to identify additional markers (rather unsuccessfully) to localize this gene precisely—which became PKD1 once it was clear that ADPKD was a genetically heterogeneous disease. In 1987, I moved as a postdoctoral fellow to Oxford, whereupon Reeders rapidly left for Yale, leaving me an unexpected degree of freedom. Doug Higgs (a molecular hematologist interested in genomics) took me under his wing, and I found a home in the Institute of Molecular Medicine of David Weatherall (now the Weatherall Institute of Molecular Medicine). Higgs taught me the importance of observation, of asking important questions, and of building a patient base to support the project. Despite Weatherall's attempts to redirect my career away from PKD, he helped establish collaborations with Peter Ratcliffe and, in turn, with Chris Winearls, the clinical director of the Oxford Kidney Unit. This was the start of a long and fruitful collaboration to characterize the Oxford ADPKD population; however, the first few years in Oxford were less focused on PKD and more on characterizing the vagaries of human telomeres and their role in chromosome rearrangements.4,5


PKD1 Gene Identification

ADPKD was pulled sharply back into focus following a call in 1992 from a medical geneticist from Cardiff, Julian Sampson, describing a Portuguese family segregating a chromosome 16:22 translocation with PKD and a second dominant disease, tuberous sclerosis (TSC). Although ADPKD seemed to be the perfect disease for positional cloning, many large families available and clear diagnostics possible by imaging in adults, the lack of informative recombinants, and the gene-rich subtelomeric region that PKD1 lay in made identification of the gene problematic. Initial analysis of the Portuguese family showed the translocation breakpoint was in the PKD1 candidate region and that individuals with the balanced exchange had PKD, whereas the son, missing the derivative chromosome containing the tip of 16 and part of 22, had TSC. Since this family promised to pinpoint the location of PKD1 and to help find the TSC gene, TSC2, we formed a Consortium of European Groups (also involving Martijn Breuning's and Dicky Halley's groups from the Netherlands) for these purposes. A consortium like this with very focused and specific goals can be remarkably productive; certainly these were very exciting, if nerve-wracking, times. The region was rapidly cloned as cosmids, mapped and characterized, and genes were sought by hybridization to cDNA libraries (Table 1). Remarkable progress was made with the hard work in Oxford of Chris Ward, Jim Hughes, Belen Peral, and our consortium partners. A number of large deletions identified the TSC2 gene.6PKD1 itself was identified as a large gene intersected by the translocation breakpoint that lay within a complex duplicated area and, remarkably, immediately tail-to-tail with TSC2, the polyadenylation sites just 60 bp apart.7,8 Because the majority of the gene lay within the duplicated area, the initial publication described only partial sequence and a handful of mutations to identify it as the disease gene. It was not for another year that the full-length sequence was revealed by amplification of the gene from a radiation hybrid containing the tip of 16p (including PKD1) but not the PKD1-pseudogenes located more proximally on 16p9 (Table 1; Figure 1). The 5′ end of the gene to exon 33 lay within the duplicated area with greater than 98% identity between PKD1 and the pseudogenes. We now know from completion of the Human Genome Project that there are six pseudogenes (PKD1 P1 through P6) that are variously rearranged relative to PKD1. They express transcripts but seem to have early mutations that prevent large protein products from being generated.7 The second ADPKD gene, PKD2, was identified by Stefan Somlo's group in 1996 with homology between the predicted PKD1 and PKD2 proteins (polycystin-1 and −2), highlighting it from others in the candidate region.10

Molecular Diagnostics and Genotype/Phenotype Correlations in ADPKD

Molecular diagnostics was hampered by the complex genomic region encoding PKD1, and, in the first few years, the focus for mutation screening was PKD2 and the single-copy exons of PKD1 (34 through 46).11,12 Eventually, methods exploiting the rare base-pair differences between PKD1 and PKD1 P1 through P6 allowed specific amplification of PKD1.13,14 Around this time, I was recruited by Vicente Torres to Mayo Clinic. Torres's great knowledge of PKD plus his enthusiasm and assembled Mayo PKD population have made this a very productive collaboration. Several full screens of PKD1 and PKD2, including those spearheaded by Sandro Rossetti at Mayo, have now been described, with a clinical molecular test available.15,16 In a clinically derived population, approximately 85% of families have PKD1 and approximately 15% have PKD2.16 Base-pair mutations have been detected in up to 87% of patients, whereas larger deletion/duplication mutations account for approximately 4% of cases.17 Both PKD1 and PKD2 are marked by extreme allelic heterogeneity with even the most commonly described mutations (PKD1: 5014delAG; PKD2: R306X and R872X) individually representing only a little more than 1% of the ADPKD population. A database of ADPKD mutations is hosted at Mayo, and details of described mutations are shown in Figure 1.18 Approximately 70% of ADPKD mutations are predicted to truncate the protein, with 30% in-frame, mainly missense variants. Algorithms have been developed to differentiate pathogenic substitutions from neutral variants.16 Deletions that disrupt PKD1 and the adjacent TSC2 result in a contiguous gene syndrome characterized by various TSC phenotypes plus more severe renal cystic disease than found in PKD1 (or TSC2) alone.17,19,20

Knockout models indicate that in utero cyst development is associated with complete loss of polycystin-1 or −2, with evidence also from ADPKD cyst linings that somatic mutation is important for cystogenesis—a two-hit model of disease.2123 However, cyst development in hypomorphic Pkd1 models expressing <20% of normally spliced product plus cysts in overexpressing transgenics suggest that the relative dosage of the polycystin protein may also be important.2426 Recently, we identified two consanguineous families homozygous for likely pathogenic missense changes.27 These variants in the heterozygous state are associated with the development of a few cysts, suggesting that they are incompletely penetrant alleles. Inheritance of such an allele in trans with a truncating PKD1 mutation is associated with early-onset ADPKD, suggesting these alleles can significantly modify the phenotypic expression of the disease and highlight that the dosage of functional polycystin may be relevant in human ADPKD.27

Gene type is a major determinant of disease severity in ADPKD, with PKD1 associated with significantly more severe disease than PKD2 (average age at ESRD of 54.3 yr compared with 74.0 yr).28 The Consortium of Radiologic Imaging Studies of PKD (CRISP) monitored early disease progression in 241 patients with ADPKD by yearly determination of total kidney and cyst volume by magnetic resonance imaging. During a 3-yr period, volumes were found to increase at an exponential rate, with an average 5.27% increase in kidney volume per year.29 Patients with the largest volumes (>1500 ml) had a significant decrease in GFR (4.33 ml/min per yr), indicating that larger volumes are emblematic of more severe disease. Several clinical trials now use change in renal volume as the primary end point to monitor disease progression. In CRISP, PKD1 kidney volumes (corrected for age and gender) were almost twice the size of PKD2 (1041 versus 623 ml),30 although there was no significant difference in the rate of growth of the kidneys (5.68%/y for PKD1; 4.82%/y for PKD2; P = 0.24). We therefore tested whether the number of cysts was significantly different and counting cyst number from a single magnetic resonance slice showed that PKD1 kidneys had more cysts than PKD2 (31.5 versus 17.0; P < 0.001). This was especially true at a young age, suggesting that PKD1 kidneys are larger because more cysts develop earlier.

The role that allelic effects play in ADPKD is less clear. Mutation type is not associated with the severity of disease in PKD1 or PKD231,32; however, the position of the mutation in PKD1 (5′ or 3′) is associated modestly with the severity of disease and propensity to develop intracranial aneurysms, although the mechanism is unclear.31,33 ADPKD displays a wide range of intrafamilial phenotypic variability. In rare cases, mosaicism or hypomorphic alleles may contribute to extreme intergenerational differences,17,27,34 but it is likely that genetic background accounts for a significant degree of this variability. Recent progress in the development of high-resolution single-nucleotide polymorphism arrays will allow genome-wide studies to look for associations between common variants and the severity of disease in large, well-characterized ADPKD populations.

ADPKD Proteins Polycystin-1 and −2

The major outcome from finding a disease gene is identification of the primary defective protein. As is the case with ADPKD and the polycystins, this can lead to the identification of a hitherto unknown protein family. Polycystin-2 is a distant member of the transient receptor potential (TRP) family of ion channels, TRPP2 (Figure 1).10,35,36 As with other TRP channels, it has six transmembrane domains and is thought to act as a homo- or heterotetramer. It is a nonselective cation channel that transports Ca2+ and is modulated by intracellular Ca2+ levels. Polycystin-2 localizes to the endoplasmic reticulum, where it may modulate levels of intracellular Ca2+ and the primary cilium.37,38 It is thought to complex with its bigger brother polycystin-1. Polycystin-1 has 11 transmembrane domains (the final six homologous to polycystin-2), a large extracellular region, and a short cytoplasmic tail (Figure 1).9,39 The extracellular region consists of a number of domains associated with protein–protein or protein–carbohydrate interactions, 16 copies of a novel lg-like fold (PKD domain), and a receptor egg jelly (REJ) domain with homology with the REJ family of sea urchin proteins.4042 Cleavage of the protein occurs at the G protein coupled receptor proteolytic site (GPS) domain, and cleavage and translocation of part of the C-tail to the nucleus has also been described.4345 Although polycystin-1 has been localized to sites of cell–cell and cell–matrix interaction, the primary cilium is likely a functional site associated with PKD (see next section).38 A total of five human polycystin-1–like and three polycystin-2–like proteins are known. PKD1L3 and PKD2L1 encode the sour taste receptor, whereas PKDREJ is involved in reproductive selection.46,47

ADPKD Is a Ciliopathy

Various pieces of data indicate that PKD is associated with defects of the primary cilium. The primary cilium is a hair-like organelle rooted in the mother centriole (the basal body) that projects from the surface of the cell and is thought to have a sensory function.48Caenorhabditis elegans homologs of PKD1 and PKD2 are involved in male mating behavior and specifically localize to cilia of sensory neurons.49 The Chlamydomonas ortholog of the protein defective in the Tg737 model of PKD (IFT88) is involved in cargo transport within cilia/flagella (intraflagella transport), and the Tg737 mouse has shortened renal cilia.5052 Conditional inactivation in the collecting duct of the intraflagella transpor kinesin II motor subunit KIF3A results in progressive cyst development after birth; cystic cells lack primary cilia.53 Cilia may act as flow sensors in kidney tubules with increased flow associated with a Ca2+ influx into the cell.54 Analysis of Pkd1−/− cells—and with an antibody blocking polycystin-2—indicates that the polycystin complex on the cilium acts as a flow sensor and that loss of either protein abolishes the flow-dependent Ca2+ influx occurring through the polycystin-2 channel.55

Cellular Changes in PKD and Prospects for Therapy

Consistent with the polycystin complex having a role in Ca2+ regulation, PKD cells display altered intracellular Ca2+ homeostasis.56 In addition, increased levels of cAMP seem to be a characteristic of PKD cells that may be directly related to changes in Ca2+ homeostasis.5759 In PKD cells, cAMP stimulates MAPK/ERK signaling compared with an inhibitory response in normal cells.60,61 As well as activating the MAPK/ERK pathway and cell proliferation in PKD cells, cAMP stimulates chloride-driven fluid secretion. Another change consistently found in PKD cells is upregulation of mammalian target of rapamycin (mTOR). It has been suggested that tuberin, the TSC2 protein (that is a regulator of mTOR), and polycystin-1 interact.62 Development of more severe disease when both PKD1 and TSC2 are disrupted by contiguous deletion suggests cross-talk between the polycystin-1 and tuberin signaling pathways.

A wide range of potential therapies have shown promise in PKD animal models. These target some of the cellular changes associated with PKD, including increased proliferation and altered fluid secretion (for review, see reference63). Those that are already in Phase 3 clinical trials include a range of mTOR inhibitors effective in animal models.62 In addition, patients who had ADPKD and underwent transplantation and received mTOR inhibitors as immunosuppressive agents saw a size reduction of the native kidney and liver.62,64 The other agents in Phase 3 trials are those targeting the heightened cAMP levels in PKD. This includes vasopressin receptor antagonists that were effective at limiting renal cystic disease in three animal models.57,58 Octreotide, a long-acting somatostatin analog was also effective at inhibiting cystic growth in both the liver and the kidney in an animal model and in preliminary data from humans.65,66 Several additional potential therapies are likely to enter clinical trials in the next few years.


Identification of PKHD1

Our interest in the mainly infantile form of PKD, ARPKD, came from the study of a rat model of PKD, PCK. This recessively inherited model, the result of a spontaneous mutation, has progressive cystic disease of both kidney and liver.67 In this case, an enthusiastic nephrology fellow/PhD student, Marie Hogan, mapped the gene in a cohort of 469 F2 animals in 2001.68 The region on rat chromosome 9 is syntenic to the human chromosome 6 interval where the ARPKD gene, PKHD1, had been mapped. Although PKHD1 was initially mapped to a chromosome region in 1994, precisely localizing it and identifying the gene was hampered by the small size of families with ARPKD, with few multiplex families (lack of recombinants), and because the sequence of the candidate region was not completed by the Human Genome Project.69,70 The greater genetic power of the rat cohort coinciding with the initial posting of the candidate region genomic sequence in 2001 enabled Hogan and Chris Ward to localize the gene to a 470-kb region.68 Northern analysis in mouse with EST clones flanking the region demonstrated a large gene (13-kb transcript) spanned the region and was hence a strong PKHD1 candidate. Using an reverse transcription–PCR approach linking predicted exons, Ward expertly and rapidly cloned the entire human transcript and Rossetti screened a few hastily collected patients with ARPKD to identify the first mutations; hence, PKHD1 was identified (Table 1; Figure 1). There has been considerable speculation about alternative splicing as a result of identification of multiple reverse transcription–PCR products and problematic Northern analysis in humans (not mouse), but little data about the significance of these alternative forms are available.71

Mutation Screening and Genotype/Phenotype Correlation

Details of described mutations are shown in Figure 1, with one mutation of likely European origin, T36M, accounting for approximately 17% of mutant alleles.7275 In contrast to ADPKD, only approximately 40% of mutations are predicted to truncate the protein with approximately 60% in-frame (mainly missense). There is little evidence of genetic heterogeneity in typical ARPKD, but genotype/phenotype correlations related to allelic events are clearly evident. All described cases with two truncating mutations have the most severe disease, dying by the neonatal period with respiratory problems.72,73 Viable cases have at least one missense change, indicating that many missense changes are incompletely penetrant alleles that presumably generate some functional protein. These findings contrast with rodent models of ARPKD where complete inactivation, although associated with liver disease similar to human ARPKD, generally results in only mild renal disease compared with the dramatic in utero cystic expansion associated with complete protein loss in humans.76,77 Further natural history studies of human ARPKD showed that, although in utero–onset disease with massive renal enlargement is typical, presentation later in childhood or even as adults is relatively common.78,79 In these cases, kidney enlargement is typically less marked, with complications of portal hypertension and bile duct dilation more often the presenting phenotype.

Fibrocystin, the ARPKD Protein

Fibrocystin is a large type 1 membrane protein with a short cytoplasmic tail and extensive extracellular region (Table 1; Figure 1).68,71 Similar to polycystin-1, a significant proportion of the extracellular region consists of repeats (12) of an lg-like fold, this time the TIG/IPT domain. One PKHD1 homolog, PKHDL1 (encoding fibrocystin-L), that shows homology over almost the entire length of the protein but is not associated with ARPKD, has been identified.80 Fibrocystin was found in the same complex as polycystin-2 and localized to cilia and the basal body.8186 Interestingly, loss of fibrocystin is associated with shorter cilia and structural abnormalities.77,87,88 Furthermore, these cilia are often surrounded by small vesicles (approximately 100 nm), whereas these vesicles are only rarely seen in wild-type mice.77 Mark Knepper's group has highlighted that vesicles, including exosomes from the multivesicular body pathway, are common in urine and can be a source of renal proteins as disease biomarkers.89 Polycystin-1 was identified as one such exosomal protein, and we speculated the vesicles seen in the ARPKD model may be urinary exosomes. Ward and Hogan have now shown that a fraction of urinary exosomes are enriched not only for polycystin-1 but also polycystin-2 and fibrocystin.90 An analysis of these PKD exosomes identified a specific proteome partially overlapping with previously described total exosome and total urine proteomes. Cleavage of the in vivo polycystin-1 (at the GPS cleavage site) and fibrocystin (at a proprotein convertase site) has been demonstrated. In vitro studies indicate these PKD exosomes interact with cilia and may play a role in the flow response or a wider role in urocrine signaling.


Identification of MKS3

The identification of a third PKD gene occurred in the modern era of complete human genomic sequence and full gene annotation (Table 1). In this case, the disease was Meckel syndrome (MKS; or Meckel-Gruber syndrome), a recessively inherited, lethal syndrome characterized by renal cystic dysplasia, occipital encephalocele, polydactyly, and biliary dysgenesis. Our interest in this disease came again from a rat model of PKD, wpk, that was first described in 2000 and further characterized by Vince Gattone to have a central nervous system (CNS) defect of agenesis of the corpus callosum.91,92 The Wpk gene was already known to lie on rat chromosome 5, and analysis of 566 F2 animals (as a collaboration with Gattone) refined the interval to a 0.6-cM, 2.05-Mb region.93 The syntenic interval contained 13 conserved genes, and sequence analysis by two summer students, Erin Goranson and Stacie Lilliquist, under the guidance of Mark Consugar, identified a nonconservative substitution (P394L) in one (LOC313067). At the same time, Colin Johnson localized an MKS locus, MKS3, to a 12.5-Mb region that was syntenic to the Wpk candidate region (8q21–22). Given the phenotypic similarity between MKS and wpk, we informed Johnson of our candidate, and, on screening, he found mutations in five families.93 A second MKS gene, MKS1, was described in the same issue of Nature Genetics, which is particularly common in Finland.94

Genetic Complexity of MKS

Follow-up genetic studies by Consugar in mainly nonconsanguineous US and Dutch families showed that both MKS1 and MKS3 are a common cause of MKS in these populations (Figure 1).95MKS3 is only rarely associated with polydactyly and in some cases with a milder CNS phenotype. Subsequent genetic studies worldwide have shown a total of nine genes associated with MKS (reviewed in reference63) (Figure 2). Additional genetic complexity has been shown with hypomorphic MKS3 alleles associated with the viable Joubert syndrome,96 whereas MKS1 mutation is linked with Bardet-Bidel syndrome97 (Figure 2). Indeed, it is now clear that a group of syndromic disorders associated with PKD, plus CNS, digital, and/or eye defects are related not only by overlapping phenotypes but also by considerable genetic overlap. Allelic effects may explain some of the phenotypic differences associated with mutation to the same gene, but oligogenic inheritance and genetic background, including modification by hypomorphic alleles, also seem important.97100

Syndromic Forms of PKD Are Ciliopathies

Localization of the proteins in these syndromic disorders to the basal body and/or cilium likely explains the range of phenotypes as they are associated with ciliary defects (Figure 2).48 The connecting cilium in the eye is essential for formation of the outer segment, and disruption leads to retinal defects. The cilium, although an important antenna detecting flow, is also essential for the function of several developmental pathways, including Hedgehog (Hh) and Wnt. Defects in the Hh pathway are associated with digital and craniofacial abnormalities, as seen in several of these disorders.101103 The PKD-associated protein, inversin, is a pivotal switch between the canonical and noncanonical Wnt pathways.104 The noncanonical pathway, also known as planar cell polarity (PCP), is important for organizing polarity across a cellular layer. PCP plays a role in neural tube closure and hence may be involved in the exencephalic phenotypes found in MKS.105 PCP is also important for tubule formation by orienting the mitotic spindle so that division occurs along the length of the tubule. Misorientation of the spindle has been seen in PKD animal models, suggesting that defects in PCP are a cause of tubule dilation as is seen in diseases such as ARPKD.106


Illustrated here are three examples of PKD whereby identification of the disease gene was the first step toward understanding pathogenesis. Completion of the Human Genome Project, atypical patients, and animal models have greatly aided gene identification. Identification of the disease gene has also aided molecular diagnostic that is now routinely available in many of these disorders. A surprising finding is the likely relatedness of PKD pathogenesis in different forms of the disease: That defects in ciliary function are likely central to pathogenesis. It is of note that discoveries in primitive model systems such as Chlamydomonas and C. elegans, plus studies of rodent models, revealed the central role of cilia in these disorders. New protein families, the polycystins and fibrocystins, have been identified, and the normal role of these proteins is now being elucidated. Understanding their function and the cellular changes associated with PKD has revealed multiple points where therapeutic intervention may be possible. Many such interventions have been shown to be effective in animal models, and several have progressed to clinical trials. The prospects for effective therapies look infinitely brighter than when we started down the road of gene identification more than 20 yr ago.



Figure 1:
Summary of the genes, proteins, described mutations, and genotype/phenotype correlations associated with ADPKD, ARPKD, and MKS (only the MKS3 gene and protein are shown). Details of the mutations come from the ADPKD Mutation Database18 (ADPKD), ARPKD Mutation Database74 (ARPKD), and various articles describing MKS mutations.
Figure 2:
Summary of genes (left) and phenotypes (right) associated with various forms of PKD. A wide range of genetic and phenotypic overlap is seen in the syndromic diseases.
Table 1:
Comparison of phenotypes, gene identification, and characteristics of the genes/proteins in three forms of PKDa

Apart from those named specifically in the text, I thank the many skilled and highly motivated scientists whom I have worked and collaborated with over the past 25 years. These include Magdalana Adeva, Richard Aspinwall, Bob Bacallao, Kyongtae Bae, Jason Bakeberg, Nicki Barton, William Bennett, Sarah Blair-Reed, Jim Bost, Arlene Chapman, Dominique Chauveau, Eliecer Coto, Peter Czarnecki, Brian Dawson, Vicki Gamble, Berenice Gitomer, Jared Grantham, Matt Griffin, Lisa Guay-Woodford, Cynthia Hommerding, Katharina Hopp, James Ireland, Bernard King, Vickie Kubly, Sumedha Kumar, Donna Lager, Nicholas LaRusso, Amanda Leightner, Luca Manganelli, Anatoliy Masyuk, Tatyana Masyuk, Catherine Meyers, Phil Miller, Dawn Milliner, Steve Mooney, Albert Ong, Priyanka Patel, York Pei, Ron Perrone, Dorien Peters, Justin Peters, Lynn Pritchard, Rachaneekorn Punyashthiti, Qi Qian, Stephanie Richardson, Dick Sandford, Robert Schrier, Tam Sneddon, Dorothy Spencer, Lana Strmecki, Blagica Tanaskovska, Sandra Thomas, Roser Torra, Han-Fang Tuan, Denise Walker, Angela Wandinger-Ness, Yu Wang, Shelly Whelan, Andrew Wilkie, Phomphimon Wongthida, John Woollard, Wai Chong Wong, Eric Wu, David Yuan, Klaus Zerres, and Jing Zhou. In addition, I thank the many patients who have taken part in our various studies and the referring physicians and genetic counselors. Finally, I thank National Institute of Diabetes and Digestive and Kidney Diseases, PKD Foundation, Mayo Foundation, MRC, and the Wellcome Trust for financial support of this work and colleagues at Mayo and Oxford for constant support.

Published online ahead of print. Publication date available at www.jasn.org.


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