The Position of the Polycystic Kidney Disease 1 (PKD1) Gene Mutation Correlates with the Severity of Renal Disease
Sandro Rossetti*,
Sarah Burton,
Lana Strmecki*,
Gregory R. Pond,
Joe L. San Millán,
Klaus Zerres¶,
T. Martin Barratt|,
Seza Ozen#,
Vicente E. Torres*,
Erik J. Bergstralh,
Christopher G. Winearls and
Peter C. Harris*
*Division of Nephrology and Section of Biostatistics, Mayo Clinic, Rochester, Minnesota; Renal Unit, The Oxford Radcliffe Hospital, Oxford, United Kingdom; Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain; ¶Institute für Human Genetik, Universitütsklinikum der RWTH Aachen, Aachen, Germany; |Institute of Child Health, London, United Kingdom; #Department of Pediatric Nephrology, Hacettepe University, Ankara, Turkey.
Correspondence to: Dr. Peter C. Harris, 760 Stabile Building, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: 507-266-0541; Fax: 507-266-4071; E-mail: harris.peter{at}mayo.edu
ABSTRACT. The severity of renal cystic disease in the majorform of autosomal dominant polycystic kidney disease (PKD1)is highly variable. Clinical data was analyzed from 324 mutation-characterizedPKD1 patients (80 families) to document factors associated withthe renal outcome. The mean age to end-stage renal disease (ESRD)was 54 yr, with no significant difference between men and womenand no association with the angiotensin-converting enzyme polymorphism.Considerable intrafamilial variability was observed, reflectingthe influences of genetic modifiers and environmental factors.However, significant differences in outcome were also foundamong families, with rare examples of unusually late-onset PKD1.Possible phenotype/genotype correlations were evaluated by estimatingthe effects of covariants on the time to ESRD using proportionalhazards models. In the total population, the location of themutation (in relation to the median position; nucleotide 7812),but not the type, was associated with the age at onset of ESRD.Patients with mutations in the 5' region had significantly moresevere disease than the 3' group; median time to ESRD was 53and 56 yr, respectively (P = 0.025), with less than half thechance of adequate renal function at 60 yr (18.9% and 39.7%,respectively). This study has shown that the position of thePKD1 mutation is significantly associated with earlier ESRDand questions whether PKD1 mutations simply inactivate all productsof the gene.
Autosomal dominant polycystic kidney disease (ADPKD) is themost common monogenetic nephropathy (frequency, 1/1000) andan important cause of end-stage renal disease (ESRD), accountingfor 5 to 8% of patients requiring renal replacement therapies(1). The disease is progressive, with cyst development and expansiontypically resulting in ESRD in late middle age. Linkage analysesin ADPKD families have revealed genetic heterogeneity with twogenes, PKD1 (chromosomal region 16p13.3) and PKD2 (4q21-q23)identified and characterized (2–5). The protein productsof PKD1 and PKD2, polycystin-1 and polycystin-2, respectively,share sequence homology and may form components of a receptor/channelcomplex (5,6). Polycystin-2 is similar to, and can functionas, an ion channel subunit, with nonselective cation permeability(6–8). Polycystin-1 is predicted to have a receptor-likestructure, may be involved in cell:cell/matrix interactions(9,10), and may have a regulatory role over a polycystin channel(6). The basic defect in ADPKD could be in polycystin-regulatedintracellular Ca2+ levels (11).
The presentation of ADPKD is highly variable, with rare casesdiagnosed in utero with massively enlarged and cystic kidneys(12,13), and 25% of cases have adequate renal function at 70yr (14). Part of the phenotypic variability is due to the geneticheterogeneity, with the more common PKD1 (accounting for approximately85% of cases; reference 15) associated with significantly moresevere disease (ESRD occurring on average at 53 yr comparedwith 69 for PKD2; reference 16). However, evidence of significantintrafamilial phenotypic variation, especially evident in pedigreesof early onset cases but also seen in the typical population,suggests that modifying factors (as well as the environment)influence the disease course (12,17–19). Data suggestingthat the angiotensin-converting enzyme (ACE) insertion/deletionpolymorphism may be such a modifier in ADPKD has been described(20,21).
Despite the intrafamilial variability in ADPKD there is evidencethat the germline mutation may influence the phenotype. Significantinterfamilial phenotypic differences have been described, andclinically mild PKD1 families documented (22–24). Furthermore,it has been suggested that the location of the PKD2 mutationinfluences the clinical outcome (25). An anecdotal associationof a specific mutation in three families with early onset diseaseand/or associated vascular complications has also been reported(26). In other genetic disorders with a variable presentation,careful analysis of large genetically defined populations hasdemonstrated correlations between phenotype and the type and/orposition of the mutation (27).
Until recently, the size and complexity of PKD1 has precludedmutation analysis of the whole gene; hence, comprehensive genotype/phenotypecorrelations have not been possible. We have now overcome theproblems associated with analysis of PKD1 and have describeda mutation screen of the entire gene (28). That study showeda wide variety of different mutations spread throughout thegene, although they were significantly more common in the 3'compared with the 5' half. We describe here an analysis of renaldisease in this mutation-characterized population and show,despite significant intrafamilial variability, that the locationof the mutation is a significant indicator of disease severity.
PKD1 Pedigrees
The proband from each family was recruited through the OxfordRenal Unit (68 pedigrees), other adult nephrology departments(5 pedigrees), or various pediatric nephrology units (7 pedigrees).All individuals involved in the study gave informed consent,and the project had ethics committee approval. All probandshad ADPKD by defined ultrasound criteria (29). Family historieswere taken, and all available family members contacted. Medicalhistories and blood samples for DNA isolation were collectedfrom family members wishing to take part in the study. Wherepossible, clinical details were verified from medical recordsor death certificates. Abdominal ultrasound was organized forat-risk patients who wished to be diagnosed. The onset of ESRDwas defined as the time when renal replacement therapy beganor death from uremia occurred. Serum creatinine (SC; µmol/L)measurements were used to assess renal function in patientsnot having ESRD. Hypertension was defined as when hypertensivetherapy was required.
Clinical Details of PKD1 Pedigrees with Atypical Presentations
Atypical renal presentations of PKD1 were defined as early onsetin cases with enlarged hyperechoic kidneys before 2 yr of age,or late onset in patients with adequate renal function at >75yr.
P117: The clinical details of members of this pedigree havepreviously been described in reference 19 (mutation Y3818X).
P118: The proband died immediately postnatally with pulmonaryhypoplasia and grossly enlarged kidneys. The mother was diagnosedby ultrasound examination and had normal renal function at 25yr (8126ins20).
P148: The proband was diagnosed in utero withgreatly enlargedkidneys. At 19 yr, her kidneys remain enlargedbut renal functionis normal. Her sister has impaired function(SC, 218 µmol/L)at 14 yr and is hypertensive. Their mother(46 yr) has normalrenal function but enlarged kidneys and polycysticliver disease.The aunt (46 yr) has normal kidney function andan affecteddaughter with normal function (18 yr). The affectedgrandmotherstarted dialysis at 54 yr (E2771K). Reference 30.
P159: The proband was diagnosed at 2 yr with gross hematuriaand ultrasound examination showing multiple cysts and renalenlargement. His father has multiple renal cysts (30 yr) (S75F).
P169: The proband was diagnosed in the first week of lifewithenlarged kidneys but has normal renal function at 7 yr.Hersister (2 yr) and mother (30 yr) have asymptomatic ADPKD.Theaunt has hypertension, and affected grandmother died frommetastasesof renal carcinoma at 49 yr. The affected great-grandmotherdied of chronic renal failure at 40 yr (7211ins7).
P190: Theproband presented at birth with enlarged kidneys,had earlyhypertension, and has slowly progressing renal failureat 15yr. The affected father has multiple renal cysts but normalrenal function (39 yr) and a negative family history (8507ins12).
P499: The proband was diagnosed by intravenous pyelography afterminor hematuria at 70 yr and ultimately developed ESRD at 80(S225X). He has an affected son (49 yr) with normal renal function(SC, 78 µmol/L).
P228: The proband had a SC of 130 µmol/Lat 81 yr, andher affected children and niece had only slightlyelevated SCof 135, 121, and 111 µmol/L at 63, 57, and46 yr, respectively(L2816P).
Molecular Data
DNA isolation procedures, mutation screening methods, and themutations identified in these pedigrees have been describedelsewhere (28). Mutations were defined as follows: truncating(nonsense, frameshifting deletions, insertions, or splice events);in-frame (insertions and splicing events that maintain the readingframe, ranging from loss of a single codon to deletion of 97residues; reference 28); or missense substitutions.
Analyses of the ACE Polymorphism
The ACE insertion/deletion (I/D) polymorphism was analyzed byPCR as described previously (20). The amplified product was190 bp (D allele) or 490 bp (I allele). An additional insertion-specificamplification was performed in all apparent D/D individualsto prevent mistyping (20). PCR products were visualized by ethidiumbromide staining after electrophoresis in 1.75% agarose gels.
Statistical Analyses
Time from birth to ESRD (or death) was computed by using theKaplan-Meier method. The effects of covariates on time to ESRDwas tested by using the univariate Cox proportional hazardsmodel or the log-rank test for continuous or categorical variables,respectively (31). Potential correlation within members of thesame family was accounted for and significance tested usinga robust variance estimator (32). The functional form of therelationship between nucleotide location and risk of ESRD wasinvestigated by plotting the Martingale residuals (from a Coxmodel with no covariates) with a local regression (LOESS) smoother,against nucleotide location (33). All tests were two-sided,and a robust P < 0.05 was considered statistically significant.In Figure 2, the running average of age at ESRD is based onthe best fitting cubic spline function of the age versus nucleotiderelationship.
Figure 2. Plot of age at onset of ESRD (orange) or age of patients with renal function (censored; green) compared with the position of the mutation along the transcript. A running average of age at onset of ESRD is plotted using only the patients with ESRD (orange).
The PKD1 Population
Information about renal status was collected on 324 PKD1 patientsfrom 80 different pedigrees in which the PKD1 mutation was characterized(28). The age at the onset of ESRD was known for 152 patients,and the age at death, not due to ESRD or for unknown reasons,was documented for an additional 36 patients. The remaining136 patients had adequate renal function, and their age andSC were recorded. Of the total population, 177 (54.6%) werewomen and 147 (45.4%) were men. There were 207 patients whoseBP status was known, of whom 147 (71.0%) were hypertensive.
To characterize the severity of disease in the PKD1 populationand to compare it with other PKD1 populations defined by linkage,survival curves from birth until ESRD, or ESRD or death, werecomputed by using the Kaplan-Meier method. The median age atthe onset of ESRD was 54 yr, and ESRD or death was 53 yr (Figure 1A).As we wished to determine what factors influenced the severityof renal disease, the age at onset of ESRD was used as the endpointin all other survival plots. Comparison of genders showed nosignificant difference (Figure 1B and Table 1). To see if theACE polymorphism was associated with disease severity in thismutation-defined PKD1 population, this marker was typed in 216patients from whom DNA was available. Of these, 64 were DD (29.6%),108 ID (50.0%), and 44 II (20.4%), giving allele frequenciesof 54.6% (D) and 45.7% (I) and a distribution in Hardy-Weinbergequilibrium. Renal survival analysis showed no significant differenceamong the three haplotypes (Figure 1C and Table 1).
Figure 1. (A) Cumulative probabilities of survival to end-stage renal disease (ESRD) or ESRD or death. Neither gender (B) nor the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism (C) have a significant influence on renal survival.
Intrafamilial and Interfamilial Variability
To analyze the extent to which the severity of renal diseasevaried within families, the age at onset of ESRD, or the ageof patients with renal function (censored data), was plottedagainst the position of the mutation within the transcript (Figure 2).This figure illustrates that the severity of disease variesconsiderably between patients with mutations in similar locations,including those within the same family (which are plotted atthe same nucleotide position). This intrafamilial variabilityprobably reflects a combination of genetic modification andenvironmental factors. To determine if the renal outcomes amongfamilies were significantly different, a Kaplan-Meier renalsurvival plot was generated for the four largest families, with17 or more patients available for study (Figure 3A; Table 1).The log-rank test showed a significant difference in time toESRD in these families (P = 0.013), with one more severe thanthe average and three with milder disease. These data indicatethat characteristics of the mutation itself may influence thedisease presentation. Genetic modification factors may, however,account for some of the interfamilial differences, althougha single factor would not be expected to have a strong influencein these large, multi-generation families.
Figure 3. Renal survival plots showing (A) significant differences in renal survival among four different PKD1 families with greater than 17 patients (mutations: P1; IVS7+1GA; P13, C2229X; P17/P17A, Q2243X, and P125, E3631D) and (B) no significant influence of mutation type (truncating, in-frame, and missense).
Analyses of the PKD1 Mutation
To test whether characteristics of the mutation were associatedwith the severity of disease, renal survival plots were comparedamong different mutation types: (1) truncating mutations; (2)in-frame changes; and (3) missense events; however, no significantdifferences were found (Figure 3B and Table 1). Second, theimportance of the mutation’s location was tested in termsof the nucleotide position along the gene with the patientsseparated into two groups at the median position (nucleotide7812; exon 19). Renal survival plots comparing the two populationsshowed that the 5' group (0 to 7812 nt) had significantly moresevere disease (P = 0.025; Figure 4A). Analysis of the plotof age at ESRD compared with mutation position demonstratedthe same result (without taking censoring into account), withthe mean age at ESRD lower at the 5' than at the 3' end (Figure 2).This difference was also reflected in the median age toESRD and probabilities of renal survival at various ages (seeTable 1 for details). Of six patients with ESRD by 35 yr, allwere in the 5' group (Figure 2). To determine the significanceof mutation location more clearly, data for each of the threemutation types was divided at the median position and analyzedseparately (Figure 4B and Table 1). This analysis showed thatlocation was associated with severity of renal disease in eachcase, with the three 5' populations associated with more severedisease than their 3' counterparts, although statistical significancewas only achieved for the in-frame mutations.
Figure 4. Renal survival plots comparing (A) patients with mutations in the 5' region of the gene (0 to 7812 nt) compared with the 3' group and (B) each mutation type (truncating, in-frame, and missense) divided at nucleotide position 7812. (C) Plot of Martingale residuals of the Cox model against nucleotide position showing a running average (red line) and zero position (black line). The overall average residual is zero with positive values, as seen in the 5' area, indicating an excess of ESRD relative to expected. All 324 patients are included, with only ESRD patients having positive residuals. Patients with location less than the median (7812) were found to have an earlier onset of ESRD (Table 1). Hence, the purpose of this exploratory analysis is to use the running average to estimate more precisely the location of a change in ESRD risk. The figure suggests a change in risk around 7 to 8 kb, near the median location. (Four points with values less than -2 are shown on the -2 axis).
To assess whether the change in disease severity along the genewas a gradual gradient or associated with a specific cut point,the Martingale residuals from a Cox model with no covariateswere plotted against nucleotide position (Figure 4C). In thisanalysis, the zero score represents an average likelihood ofdeveloping ESRD, with patients plotted above the line developingESRD earlier than the average and those below the line havingless severe disease. The running average shows a greater likelihoodof ESRD in the 5' population and a cut point to less ESRD atabout 7 to 8 kb, indicating that the median position (7812 nt)is a reasonable estimate of the point of change.
Families with Atypical Renal Presentation
The penetrance of the PKD1 phenotype, when ESRD is consideredan end point, is very high (Figure 1). However, two familiesin whom comprehensive histories were available had consistentlymild cystic disease (see Materials and Methods). Although mutationposition is an indicator of disease severity in the whole population,this does not seem to explain these extreme cases, as one hada 5' mutation and one had a 3' change. It is possible in thesecases that unusual characteristics of the mutation, such asan ability to generate a partially functional polycystin-1 fromPKD1 with a missense mutation (P228), may explain the mild disease.In the other family (P499), the mutation is a nonsense changeearly in the gene and mosaicism is possible in the father, ashe has an apparent negative family history. This was, however,not evident in leukocyte DNA, and his son also had mild disease.
This study contained six pedigrees including one early onsetcase. Two of these pedigrees had mutations in the 5' region,and four had mutations in the 3' area and were of various types(see Materials and Methods) and so the position or type of thesechanges was not a good indicator of early onset disease. Twoof these changes were also found in families with more typicaldisease (28), and there is clear intrafamilial phenotypic variabilityin the early-onset families (see Materials and Methods for clinicaldetails).
We have analyzed renal disease severity in a large and highlycharacterized cohort of PKD1 families. The median age at theonset of ESRD or death of 53 yr was similar to other studies(16), with a slightly higher age for ESRD alone (54 yr). Thisdifference reflects death from nonrenal PKD1-related problems,such as subarachnoid hemorrhage and cardiovascular disease,as well as early non-PKD1 related deaths. Consistent with otherPKD1 studies, gender was not found to correlate significantlywith disease severity (16). This finding differs from some previousstudies (34) of the entire ADPKD population, which found significantlymore severe disease in men. One explanation for the differencebetween these studies may be an influence of gender that hasbeen noted in PKD2 (16).
One of the strongest conclusions that can be drawn from thisstudy is that the presentation of the disease is highly variable,with marked differences in disease severity seen within individualfamilies. This is consistent with previous studies that haveshown significant intrafamilial variation using measures ofrenal function, renal size, and age at the onset of ESRD (17,18,35).This variation presumably reflects the significant influenceof genetic modifying factors and environment on disease presentationand progression. One possible group of modifying factors areones that effect the frequency of somatic second hits and thereforemodulate the rate of cyst initiation or influence the courseof cyst development (36). Genetic modifying factors have beenmapped in various rodent models of polycystic kidney diseaseand are likely to be important in PKD1 (37–39). Two previousstudies of PKD1 populations suggested that the ACE polymorphismmight be a significant modifier (20,21), with an associationbetween severe renal disease and the DD haplotype; one studyfound no correlation (40). In our population, no associationwas found between the ACE genotype and severity of renal disease,indicating that here the ACE polymorphism is not a significantmodifying factor. Extremes of intrafamilial variability wereparticularly evident in families with an early onset case ofdisease. The evidence presented here of a wide variety of differentmutations associated with early presentation, the documentedvariability within families, and recurrence risk in siblingsindicates that one or a small number of modifying factors (12,19),or possibly an early somatic event, are likely to strongly influencethe disease presentation in these cases. Likewise, special factors,such as only partially inactivating mutations or mosaicism (althoughthis could not explain mild disease in multiple generations)may be important in pedigrees with late-onset PKD1.
The large size of the study population and the available mutationdata allowed genotype/phenotype correlations in PKD1 to be addressedfor the first time. The most important finding from this analysiswas that the position of the PKD1 mutation influenced the severityof renal disease. The effect was modest compared with the totalamount of variability; however, it was statistically significantin the total population. It is unlikely that other factors accountedfor the association between position and severity of renal disease.Neither gender (P = 0.52) nor hypertension (P = 0.69) were significantlydifferent between the 5' and 3' populations, and the ACE haplotypewas not associated with severity of renal disease (P = 0.26).The effect of the mutation location can be seen in the plotof age at ESRD, with the running average moving upward fromthe 5' to 3' end, and the average value changing from a minimumof 49 yr in the 5' region to a maximum of 54 yr in the 3' area(Figure 2). This effect is, however, more clearly seen in arenal survival plot when data from all patients is included(Figure 4A), with a significant difference seen between the5' and 3' populations. The difference is expressed in the findingthat ESRD occurs, on average, two to five years earlier in the5' population between 25 to 70 yr, with a more pronounced differenceas age progresses (Table 1). The plot of Martingale residualsgave support to the hypothesis that a position of 7 to 8 kbalong the gene (close to the median location) marks a cut pointbetween more severe and a milder disease outcome.
Finding that the location of the mutation significantly influencesthe phenotype may have implications for understanding the diseasemechanism. It has been widely assumed, consistent with the two-hithypothesis, that regardless of type or position, the germlinemutation simply inactivates a PKD1 allele. A cyst subsequentlydevelops in the absence of polycystin-1 following a second inactivatingmutation (36). However, the finding that the location of themutation influences the disease course suggests that some productcan be generated from the mutant allele. Interestingly, previousstudies of the mutant PKD1 gene have shown that the abnormaltranscript is usually stable (not susceptible to nonsense-mediatedmRNA decay), suggesting that the mutant gene may generate afunctional product (28).
A possible explanation for the more severe disease associatedwith 5' mutations is that they generate a dominant negativeproduct. This would be consistent with the more severe diseaseassociated with 5' in-frame cases (Figure 4B). However, analysisof a family with a truncating mutation at the extreme 5' end(P103, 224del13; 28), which is unlikely to generate an abnormalproduct, shows that the affected members develop ESRD at a meanage of 47 yr (4 events) and hence appear to have the severe5' phenotype. These data seem to indicate that loss of a productrather than a dominant negative effect may be important. Morethan one protein may be generated from the PKD1 gene, and thelocation-associated phenotypic difference could be because 5'and 3' mutations disrupt different products. Possible sitesof splicing or cleavage close to the proposed phenotypic cutsite (7 to 8 kb; exons 15 to 20 in the REJ or GPS regions ofthe protein) have been described (3,4,41). Recent comparisonof two targeted disruptions of murine Pkd1 (in the 5' region,exon 4; Pkd1null and 3' region, exon 34; Pkd1del34) showed thatthe 5' mutant had a more severe phenotype in the homozygousand heterozygous animals (42). Furthermore, although the 5'mutant did not generate a polycystin-1 product when analyzedwith an N-terminal antibody, a polycystin-1 product was seenin the del34 mutant, indicating that the location of the mutationmay influence the polycystin-1 products generated. Disruptionof an N-terminal product may be more deleterious, and disruptionof the relative abundance of different splicing/cleavage productsmay be critical, as occurs at the WT1 locus (43–45). Recently,evidence that polycystin-1 dosage may be important for normalrenal development has been described (46).
This study indicates that, despite the variability of the PKD1phenotype, the position of the mutation influences the renalphenotype. Discovering the precise mechanism by which 5' and3' mutations have different phenotypic effects will requireexperimental approaches as well as further epidemiologic data.Nevertheless, this observation indicates that renal cystic diseasein PKD1 results from more than simple loss of all polycystin-1products.
Acknowledgments
We thank Drs. Lesley Rees and Sushmita Roy, London, UK; Dr.Albert O. M. Ong, Sheffield, UK; and Drs. Peter J. Ratcliffeand Tricia Boyd, Oxford, UK for supplying samples and clinicalinformation on their patients. We also thank the patients andtheir families for taking part in the study, Vicki Gamble forgenotyping analysis, C. Strong for data collection, and JeffreySlezak for statistical analysis. This work was supported byNIDDK Grant RO1 DK58816, The Medical Research Council (UK),The Mayo Foundation, The PKD Foundation, Telethon, Italy, NATO/RoyalSociety (UK), and the Oxford Kidney Unit Trust Fund.
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Received for publication October 23, 2001.
Accepted for publication December 22, 2001.
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Abstract
Introduction
2
1-integrin in focal clusters in adherent renal epithelia. Lab Invest 79: 1311–1323, 1999[Medline]
A; P13, C2229X; P17/P17A, Q2243X, and P125, E3631D) and (B) no significant influence of mutation type (truncating, in-frame, and missense).