Spectrum of Mutations in the Gene for Autosomal Recessive Polycystic Kidney Disease (ARPKD/PKHD1)
Carsten Bergmann*,
Jan Senderek*,
Beate Sedlacek*,
Ioannis Pegiazoglou*,
Patricia Puglia*,
Thomas Eggermann*,
Sabine Rudnik-Schneborn*,
Laszlo Furu,
Luiz F. Onuchic,
Monica de Baca¶#,
Gregory G. Germino,
Lisa Guay-Woodford||,
Stefan Somlo,
Markus Moser&,
Reinhard Büttner¶ and
Klaus Zerres*
*Institute of Human Genetics, Aachen University, Aachen, Germany; Medicine and Genetics, Yale University, New Haven, Connecticut; Medicine and Genetics, Johns Hopkins University, Baltimore, Maryland; Medicine, University of Sao Paulo, Sao Paulo, Brazil; ¶Institute of Pathology, University of Bonn, Germany; #Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania; ||Medicine and Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; &Max-Planck-Institute for Biochemistry, Martinsried, Germany.
Correspondence to Dr. Carsten Bergmann, Institute of Human Genetics, Aachen University, Pauwelsstrae 30, D-52074 Aachen, Germany. Phone: +49-241-8080178; Fax: +49-241-8082580;
ABSTRACT. Autosomal recessive polycystic kidney disease (ARPKD/PKHD1)is an important cause of renal-related and liver-related morbidityand mortality in childhood. Recently mutations in the PKHD1gene on chromosome 6p21.1-p12 have been identified as the molecularcause of ARPKD. The longest continuous open reading frame (ORF)is encoded by a 67-exon transcript and predicted to yield a4074–amino acid protein ("polyductin") of thus far unknownfunction. By now, a total of 29 different PKHD1 mutations havebeen described. This study reports mutation screening in 90ARPKD patients and identifies mutations in 110 alleles makingup a detection rate of 61%. Thirty-four of the detected mutationshave not been reported previously. Two underlying mutationsin 40 patients and one mutation in 30 cases are disclosed, andno mutation was detected on the remaining chromosomes. Mutationswere found to be scattered throughout the gene without evidenceof clustering at specific sites. About 45% of the changes werepredicted to truncate the protein. All missense mutations werenonconservative, with the affected amino acid residues foundto be conserved in the murine polyductin orthologue. One recurrentmissense mutation (T36M) likely represents a mutational hotspotand occurs in a variety of populations. Two founder mutations(R496X and V3471G) make up about 60% of PKHD1 mutations in theFinnish population. Preliminary genotype-phenotype correlationscould be established for the type of mutation rather than forthe site of the individual mutation. All patients carrying twotruncating mutations displayed a severe phenotype with perinatalor neonatal demise. PKHD1 mutation analysis is a powerful toolto establish the molecular cause of ARPKD in a given family.Direct identification of mutations allows an unequivocal diagnosisand accurate genetic counseling even in families displayingdiagnostic challenges. E-mail: cbergmann@ukaachen.de
Autosomal recessive polycystic kidney disease (ARPKD [MIM 263200])or polycystic kidney and hepatic disease 1 (PKHD1) is a severeinherited disorder with a proposed incidence of 1/20,000 livebirths and a widely variable clinical spectrum (1–3).Its principal manifestations involve the fusiform dilation ofrenal collecting ducts and distal tubuli and dysgenesis of thehepatic portal triad. The only signs potentially displayed inutero, albeit often not even visible in second trimester fetalsonography, are enlargement and increased echogenicity of bothkidneys as well as oligohydramnios (4–6). As many as 30to 50% of affected neonates die shortly after birth in respiratoryinsufficiency due to pulmonary hypoplasia. In ARPKD patientssurviving the neonatal period, the prognosis is more optimistic(7). Frequent complications include systemic hypertension (HTN),end-stage renal disease (ESRD), and clinical manifestationsof congenital hepatic fibrosis (CHF).
Due to the poor prognosis of early manifestations of ARPKD,there is a strong demand for prenatal diagnosis (6). An earlyand reliable prenatal diagnostic test became feasible in 1994,when the ARPKD gene was mapped to chromosome 6p21-cen (8). Withcurrent knowledge from linkage data, there is no clear evidenceof genetic heterogeneity in ARPKD. Two independent groups recentlyunraveled the PKHD1 gene (9,10). Ward et al. identified thehuman gene by homology to the mutation in the PCK rat modelfor polycystic kidney disease (11,12), and our group succeededby positional cloning (13–16). On genomic DNA, the genespreads over an expanse of at least 470 kb. A minimum of 86exons is assembled into a variety of alternatively spliced transcriptssized from approximately 8.5 kb to approximately 13 kb (10).The longest continuous open reading frame (ORF; Figure 1) isencoded by a 67-exon transcript and is predicted to yield aprotein of 4074 amino acids. The complex pattern of splicingwas found to be highly conserved in the murine orthologue (17).
Figure 1. Linear representation of the polyductin protein encoded by the longest potential open reading frame. The sites of mutations detected in this study and described in the literature are indicated. Putative polyductin domains are colored (red, signal peptide; yellow, IPT; green, PbH1 repeat; blue, transmembrane domain). The lengths of truncated peptides encoded by PKHD1 alleles with chain-terminating mutations are illustrated at the bottom.
The predicted full-length protein that we termed polyductinrepresents a novel integral membrane protein with an extensive,highly glycosylated N-terminal extracellular region, a singletransmembrane-spanning domain, and a short cytoplasmic tailcontaining potential phosphorylation sites. Polyductin mightfunction as receptor or ligand. The proposed extracellular domaincontains several IPT (Ig-like, plexin, transcription factor)domains that are shared by hepatocyte growth factor (HGF) receptorand the plexin superfamily involved in the regulation of cellularadhesion, repulsion, and proliferation (18–20). In addition,multiple PbH1 (parallel beta-helix 1) repeats are found in theputative polyductin extracellular region. PbH1 repeats are presentin virulence factors, adhesins, and toxins in bacterial pathogenesisand known to bind to carbohydrate moieties (21). In case ofpolyductin, targets for binding could include glycoproteinson the cell surface or in the basement membrane. However, definitepolyductin functions remain to be unraveled.
By now, a total of 29 different PKHD1 mutations have been described.The present study aimed at three major points: (1) to definethe underlying molecular basis in a cohort of 90 apparentlyunrelated families with at least one child affected by ARPKD;(2) to determine the achievable mutation detection rate in PKHD1;and (3) to evolve possible genotype-phenotype correlations.
Selection of the Study Population
A series of 90 apparently unrelated families with at least onechild affected by ARPKD (148 affected individuals/fetuses) wasselected for PKHD1 mutation screening. This cohort mainly consistedof families who had sought prenatal diagnosis during the lastdecade. The diagnostic criteria were the same as those reportedelsewhere (6): (1) clinical manifestation of ARPKD with characteristicultrasonographic findings (22,23) and (2) presence of at leastone of the following: (a) absence of renal cysts in parentalultrasound (this criterion was fulfilled in all but three families),(b) symptoms or histopathologic evidence of hepatic fibrosis,(c) pathoanatomical proof of ARPKD in an affected sibling, or(d) parental consanguinity. The cohort of patients studied representeddiverse nationalities from 24 mainly European countries andthe entire clinical spectrum (Tables 1 through 3). Phenotypeswere categorized as severe or moderate. The group of severecases included 44 families with perinatal or neonatal demiseof affected children (Table 1). The moderate cohort comprised38 families with patients who either survived complications(mainly respiratory) during the first month of life or becamefirst symptomatic beyond the neonatal period (Table 3). We areaware of the difficulties in establishing phenotype categorization,particularly with regard to the group of patients denoted asmoderately affected. A further subdivision of this cohort washardly feasible due to diversity of clinical presentation. Eightfamilies were characterized by marked intrafamilial phenotypicvariability among affected siblings (Table 2). DNA from the90 ARPKD families studied and 150 apparently unrelated, healthycontrol individuals was obtained after informed consent hadbeen given.
Table 3. Synopsis of ARPKD patients/families with moderate phenotype
Haplotype Analysis
Families in which a prenatal diagnosis had been establishedwere compatible with linkage to the ARPKD locus on chromosome6p. At least four informative markers from a set of 15 microsatellitesfrom the ARPKD interval had been typed in each family (10,24).After identification of a recurrent PKHD1 mutation, allele-sharinganalysis was done in the respective families to study a possiblefounder effect. Primers for PCR amplification were as publishedby the Genome Data Base (http://www.gdb.org) and by Mücheret al. (24) and Onuchic et al. (16). Sense primers were labeledwith FAM fluorophores (Pharmacia, Uppsala, Sweden) for electrophoresisand analysis on an ABI PRISM 377 genetic analyzer (Applied Biosystems,Weiterstadt, Germany).
Mutation Analysis
Mutation screening was done for the 67 exons that constitutethe longest continuous polyductin ORF. Genomic DNA from an affectedindividual of each family was amplified by PCR with oligonucleotideprimers complementary to flanking intronic sequences. Primerswere designed using the Primer3 program (http://www-genome.wi.mit.edu/cgi-bin/primer/primer3.cgi)to generate PCR products of less than 300 bp suitable for single-strandconformation polymorphism analysis (SSCP). Larger exons weresplit into up to ten overlapping fragments of reasonable sizefor SSCP. In total, PKHD1 was amplified as 90 fragments. ForSSCP screening, PCR products were run at four different conditionson 10% non-denaturing polyacrylamide gels (49:1 acrylamide:bis-acrylamidewith or without 10% glycerol) at 250 V for 2.5 to 4 h eitherat room temperature or 4°C. For visualization of bands,gels were silver stained. Samples exhibiting aberrant migrationpatterns on SSCP gels were subjected to direct sequence analysis.PCR products were gel purified with the QiaEx-kit (Qiagen, Hilden,Germany) and sequenced employing ABI BigDye chemistry (AppliedBiosystems, Weiterstadt, Germany). The same primers as for SSCPwere used as sequencing primers. Samples were run and analyzedon an ABI PRISM 310 genetic analyzer (Applied Biosystems). Whena mutation had been identified, segregation of the altered allelewas tested by direct sequencing of parental probes. DNA samplesfrom 150 apparently unrelated normal control subjects were alsotested under appropriate SSCP conditions to exclude a possiblepolymorphism in case of a potential missense mutation or subtlein-frame change.
Mutation Analysis in PKHD1
In a cohort of 90 apparently unrelated families with at leastone child affected by ARPKD, we performed a systematic mutationscreen of all 67 exons comprised in the longest continuous polyductinORF. A total of 110 out of expected 180 mutations were observed,resulting in a detection rate of 61%. We were able to disclosetwo underlying mutations in 40 individuals (45%, for examplessee Figure 2) and one mutation in 30 cases (33%). No mutationcould be found in 20 patients (22%). In all individuals foundto harbor two mutations, the mutant alleles were proven to resideon separate chromosomes (Tables 1 through 3).
Figure 2. PKHD1 mutations in families studied. Representative pedigrees are given on the left, and the mutations identified in the respective families are shown on the right. Sense strand electropherograms from the affected patients are illustrated at the top, and a limited reading frame is given below. In case of a homozygous mutation, the wild-type sequence is depicted in a separate electropherogram.
Of the observed changes, 49 were chain-terminating mutationscomprising 26 nonsense mutations, 21 deletions/insertions, and2 splice-site variants. Conclusively, about 45% of the mutationsobserved are predicted to truncate the protein. A second groupof probable mutations were non-conservative missense changesfor which segregation with the disease was proven. These alterations(total 61) were neither found on control chromosomes nor previouslydescribed as polymorphisms (9,10). All observed missense changeswere found to replace residues conserved in the murine polyductinorthologue (Table 4). All probands with putative missense substitutionswere included in the screen of the rest of the gene. No morethan a maximum of two putative pathogenic mutations were observedin all but one case. In this patient (90.1), we identified twomissense changes residing on the paternal chromosome that werenot detected in control individuals. However, one of these alterationswas a conservative exchange from isoleucine to valine, makingits pathogenic character questionable.
The mutations we detected were mostly unique and scattered throughoutthe entire gene. We observed one recurrent missense mutationin exon 3 changing the ACG codon 36 to ATG (c.107C>T; T36M).This alteration occurred in 26 obviously unrelated patientsof different ethnic origin. Allele sharing analyses proved thatat least 16 different haplotypes are responsible for the highprevalence of this mutation in the German and Finnish populations(data not shown). Interestingly, individuals 2.1 and 2.2 offamily 2 harboring T36M in the homozygous state carry differentparental haplotypes (Figure 3). As previously suggested (24),two founder alleles are responsible for about 60% of PKHD1 mutationsin the Finnish cohort. We identified the PKHD1 mutations associatedwith these two consensus haplotypes (c.1486C>T [R496X] andc.10412T>G [V3471G]). Table 4 summarizes all pathogenic changesthat were either predicted to truncate the protein or representedmissense mutations not detected in the control population. Figure 1indicates the relative location of each mutation along a linearrepresentation of the protein.
Figure 3. Haplotype analysis and the identified PKHD1 mutation in family 2. The affected child 2.1 was found to be heterozygous for microsatellite markers from the ARPKD region while homozygously carrying the T36M mutation in the PKHD1 gene.
In addition to the reported mutations, several polymorphismswere observed. Some of these have been described previously(9). Overall, SSCP detected 26 recurrent (up to 40% of chromosomes)and 7 unique aberrant migration patterns that were identifiedas polymorphisms because they were (1) intronic changes beyondthe consensus splice sites, (2) located in the 5' or 3' UTR,(3) silent exonic changes (not altering an amino acid), or (4)a substitution that did not segregate with the disease or wasfound in normal controls. Two novel missense changes (c.1736C>T[T579M] and c.2489A>G [N830S]) could be excluded as pathogenicmutations as they were also detected in about 10% of normalcontrol individuals.
Genotype-Phenotype Correlations
In the cohort of patients with a moderate phenotype, we wereable to detect 30 out of 76 mutations (40%), whereas we identified68 mutations in the 88 ARPKD alleles (77%) from individualsdisplaying a severe phenotype. Conclusively, the level of detectionwas considerably higher in patients with a severe clinical course.The detection rate observed in the group of families with phenotypicvariability among affected sibs reached 75% (12 out of 16 alleles);however, these latter figures might be biased due to the smallnumber of families screened in this cohort. Analysis of themutational spectrum in the different subgroups revealed morethan half of the mutations detected in the severe group to betruncating (40 of 68). In the moderate cohort, missense changeswere more than three times as frequent as chain-terminatingalterations (22 of 30).
Further insight into genotype-phenotype correlations shouldcome from patients homozygous for a given mutation. All individualscarrying a termination-type mutation in the homozygous statedied shortly after birth. Missense mutation R3482C was seenhomozygously in two consanguineous Israel-Arab families (297and 360) with perinatal demise in all five affected children.In three other consanguineous multiplex families (95, 188, and225), each harboring a different missense mutation, all affectedindividuals died shortly after birth. In two further inbredfamilies with single affected children carrying a homozygousmissense mutation (families 260 and 270), a moderate phenotypewas observed. Affected individuals of family 2 with the T36Mmutation in the homozygous state displayed intrafamilial phenotypicvariability.
Given that termination-type mutations all have a uniform effect,one would expect the type and position of the missense changeto determine the clinical course in compound heterozygotes withone truncating and one missense mutation in trans. Our preliminaryresults indicate that missense mutations L2134P and D2761Y areassociated with perinatal/neonatal demise. Association witha moderate phenotype was observed for missense mutation A1030Ewhile the phenotype varied in patients with I222V and V3471G.However, except for A1030E, which is located in one of the predictedIPT domains, all affected amino acids reside in regions withoutapparent homology to known protein sequences. Thus, we couldnot establish any structure-function relationship for thesemissense mutations.
The pathways involved in renal cyst formation and biliary dysgenesisin ARPKD are still widely unknown. As a vital step in unravelingthe underlying molecular pathomechanisms in this disorder, theresponsible gene was identified by two independent groups (9,10).
Novel and Known PKHD1 Mutations
Further insight into the underlying disease mechanisms in ARPKDwill be provided by both functional investigations and identificationof mutations, which will help to unravel protein regions crucialfor proper polyductin structure and function. In this study,we performed SSCP analysis on 90 patients diagnosed with ARPKDfor PKHD1 mutations and identified 110 mutations. Conclusively,the level of detection reached 61% of disease chromosomes, comparablewith detection rates achieved in the initial screen for otherlarge multiexon genes (25,26). Among the mutations identified,34 were not reported previously, expanding the spectrum of knownPKHD1 mutations from 29 to 63 (Table 4).
Mutations were dispersed over the entire gene with no evidenceof clustering at specific sites. Most of the mutations detectedare of unique character, which is in agreement with the existenceof many diverse haplotypes on ARPKD chromosomes (6,8). Of 63different mutations reported so far, only ten were found intwo or more pedigrees from the present study or in the cohortsof others (9,10). The recurrent T36M mutation in exon 3 mostprobably represents a mutational hotspot. This assumption seemsreasonable since most of the CpG dinucleotides are hypermutable,as the cytosine is often methylated and susceptible to spontaneousdeamination to form a thymidine (27). Two other recurrent mutations(R496X and V3471G) were restricted to the Finnish isolate. Atpresent, with the exception of T36M in exon 3, we have no clearproof of protein regions that should be screened initially forPKHD1 mutations in "non-isolate" populations.
In patients in whom only one or no mutation was found, it islikely that limitations of SSCP technique hampered detectionof the second or any variant. Alternatively, the remaining sequencevariations may be located in regulatory elements or in additionalexons not included in the longest ORF. These sequences havenot yet been screened. Moreover, other mutation mechanisms,e.g., gross deletions or genomic rearrangements are not detectableby SSCP. In most cases, however, gross deletions seem less likely,because we observed heterozygosity for various nonpathogenicsingle-nucleotide changes scattered throughout the PKHD1 gene.Nevertheless, deletions of single or some exons or genomic rearrangementscannot be ruled out with certainty by the methods applied. Amongthe 20 patients analyzed without any detectable mutation, locusheterogeneity has to be considered, though our own linkage data(6,8,28) and those of others (29) argue against the existenceof a second ARPKD gene. Alternatively, in some of these patientsthe assumed diagnosis of ARPKD might be incorrect. It is noteworthythat most individuals of this cohort displayed a moderate phenotypewithout pathoanatomical proof of ARPKD.
Whether the ratio observed in our study between chain-terminatingmutations (n = 49) and missense changes (n = 61) is the correctrepresentation of PKHD1 alterations remains to be clarified.It has to be noted that one of the founder alleles in the Finnishpopulation (R496X) accounts for a considerable proportion ofthe identified truncating mutations (20 out of 49). Moreover,it is conceivable that SSCP analysis will more likely detectframeshifting mutations than subtle nucleotide substitutions.Any of the missense changes (and, of course, some of the terminatingchanges as well) may have untoward effects on splicing not assayedby our methods. For example, in family 188, it might be moreplausible to assume an intron 9 donor splice site error thanan amino acid exchange from glycine to serine. Whether thishypothesis is correct needs to be established on transcriptlevel, but RNA was not accessible. On the other hand, despiteevidence from segregation analysis, screen of normal individuals,lack of further changes in the rest of the gene, and the non-conservativenature of the amino acid substitutions, it cannot be ruled outthat some of the PKHD1 missense changes reported so far willultimately be revealed as nonpathogenic alterations.
Genotype-Phenotype Correlations
Multiple allelism and the high rate of compound heterozygotesmake it difficult to establish convincing genotype-phenotyperelationships in ARPKD. Preliminary correlations could be establishedfor the type of mutation. The proportion of chain-terminatingmutations was significantly higher in the severe group (59%of identified alleles) than in the moderately affected cohort(23% of identified alleles). Given the considerable number ofFinnish patients in this study, it might be argued that theincreased prevalence of termination-type mutations in the severecohort is simply a result of the ethnic background rather thana true relationship to the phenotype. However, even after exclusionof all Finnish patients the ratio remains comparable (51% versus16%).
In this study, all individuals found to harbor two chain-terminatingmutations in trans (12 families, Table 1) died shortly afterbirth, irrespective of the site of the premature stop of translation.In family 440, we observed a homozygous frameshift mutationnear the C-terminus (I3658fsX3664), supposedly removing theunique transmembrane domain and the cytoplasmic tail while leavingmost of the extracellular portion alone. It is thus suggestedthat a critical amount of full-length polyductin is requiredfor a proper protein function. Given the multitude of missensealleles and the variety in phenotypic presentation, patientswith PKHD1 mutations will be an interesting population to studygenotype-phenotype correlations. This article provides the firstclues that some missense mutations are associated with a uniformphenotype (see Results section). However, more sustainable genotype-phenotypecorrelations will require identification of further patientsharboring a peculiar genotype. Interfamilial phenotypic variabilityis common in ARPKD and presumably based on multiple allelism.In a given family, the clinical course among affected siblingsis usually comparable (3,30); however, a small proportion ofsibships included in the present study exhibited marked intrafamilialclinical variability (Table 2). Obviously, phenotypes causedby PKHD1 mutations cannot be explained on the basis of the genotypealone, but supposedly also depend on the background of othergenes, epigenetic factors, and environmental influences. Itmight be interesting to determine whether modifier genes thatinfluence disease severity in mouse models for polycystic kidneydisease modulate the phenotype in human ARPKD (31,32). Moreover,among epigenetic factors, the process of alternative splicingmight be relevant as a modifying mechanism peculiarly in thesetting of multiple putative polyductin splice variants (33,34).
Advantages and Limitations of Direct Mutation Analysis
Due to the poor prognosis of early manifestations of ARPKD,many parents seek prenatal diagnosis. Thus far, without knowingthe PKHD1 gene, prenatal diagnosis was only feasible by indirectgenotyping. However, interpretation of haplotype-based analysismight prove difficult in cases without an unambiguous clinicopathologicdiagnosis. Notably, in three families from the present studywith identified mutations (families 264, 385, and 427), earlymanifesting autosomal dominant polycystic kidney disease hadto be considered because parental renal or hepatic ultrasoundrevealed areas suspicious of cyst formations (35). Thus, infamilies with diagnostic uncertainties, characterization ofPKHD1 mutations allows to offer accurate genetic counselingand prenatal diagnosis. However, mutation analysis in ARPKDposes special difficulties due to the huge size of the gene,multiple predicted splice variants, and marked allelic heterogeneity.Special note is warranted regarding difficulties in differentiatingpathogenic nucleotide substitutions from harmless sequence variants.Due to the aforementioned challenges and limitations of PKHD1mutation screening, haplotype determination of closely flankingand intragenic microsatellites will be further used for efficientgenotyping in families without diagnostic doubts. However, infamilies with diagnostic challenges or families in whom no DNAof the oftentimes deceased index patient is available, a directapproach will be the only option to establish a molecular geneticdiagnosis.
Acknowledgments
The authors would like to thank the patients and families aswell as their physicians who were involved in these studiesfor their cooperation. The technical assistance of ChristianeLupczyk, Edith von Heel, and Edith Bünger is gratefullyacknowledged. This work was supported by the Deutsche Forschungsgemeinschaftand by National Institutes of Health grant R01 DK51259.
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Received for publication August 2, 2002.
Accepted for publication September 13, 2002.
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417 - 429.
[Abstract][Full Text][PDF]
M. A. Garcia-Gonzalez, L. F. Menezes, K. B. Piontek, J. Kaimori, D. L. Huso, T. Watnick, L. F. Onuchic, L. M. Guay-Woodford, and G. G. Germino Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway
Hum. Mol. Genet.,
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1940 - 1950.
[Abstract][Full Text][PDF]
S. Rossetti and P. C. Harris Genotype-Phenotype Correlations in Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease
J. Am. Soc. Nephrol.,
May 1, 2007;
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1374 - 1380.
[Abstract][Full Text][PDF]
A M Sharp, L M Messiaen, G Page, C Antignac, M-C Gubler, L F Onuchic, S Somlo, G G Germino, and L M Guay-Woodford Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts
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April 1, 2005;
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[Full Text][PDF]
T. V. Masyuk, B. Q. Huang, A. I. Masyuk, E. L. Ritman, V. E. Torres, X. Wang, P. C. Harris, and N. F. LaRusso Biliary Dysgenesis in the PCK Rat, an Orthologous Model of Autosomal Recessive Polycystic Kidney Disease
Am. J. Pathol.,
November 1, 2004;
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[Abstract][Full Text][PDF]
Q. Zhang, P. D. Taulman, and B. K. Yoder Cystic Kidney Diseases: All Roads Lead to the Cilium
Physiology,
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225 - 230.
[Abstract][Full Text][PDF]
S. Wang, Y. Luo, P. D. Wilson, G. B. Witman, and J. Zhou The Autosomal Recessive Polycystic Kidney Disease Protein Is Localized to Primary Cilia, with Concentration in the Basal Body Area
J. Am. Soc. Nephrol.,
March 1, 2004;
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592 - 602.
[Abstract][Full Text][PDF]
L. M. Guay-Woodford Murine models of polycystic kidney disease: molecular and therapeutic insights
Am J Physiol Renal Physiol,
December 1, 2003;
285(6):
F1034 - F1049.
[Abstract][Full Text][PDF]
L. Furu, L. F. Onuchic, A. Gharavi, X. Hou, E. L. Esquivel, Y. Nagasawa, C. Bergmann, J. Senderek, E. Avner, K. Zerres, et al. Milder Presentation of Recessive Polycystic Kidney Disease Requires Presence of Amino Acid Substitution Mutations
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2004 - 2014.
[Abstract][Full Text][PDF]
M. C. Hogan, M. D. Griffin, S. Rossetti, V. E. Torres, C. J. Ward, and P. C. Harris PKHDL1, a homolog of the autosomal recessive polycystic kidney disease gene, encodes a receptor with inducible T lymphocyte expression
Hum. Mol. Genet.,
March 15, 2003;
12(6):
685 - 698.
[Abstract][Full Text][PDF]
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Abstract
Introduction
