Feline Polycystic Kidney Disease Mutation Identified in PKD1
Leslie A. Lyons*,
David S. Biller,
Carolyn A. Erdman*,
Monika J. Lipinski*,
Amy E. Young*,
Bruce A. Roe,
Baifang Qin and
Robert A. Grahn*
*Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California; Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas; and Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma
Correspondence to Dr. Leslie A. Lyons, 1114 Tupper Hall, Department of Population Health & Reproduction, School of Veterinary Medicine, One Shields Avenue, University of California, Davis, Davis, CA 95616. Phone: 530-754-5546; Fax: 530-752-4278; E-mail: lalyons{at}ucdavis.edu
Autosomal dominant polycystic kidney disease (ADPKD) is acommonly inherited disorder in humans that causes the formationof fluid-filled renal cysts, often leading to renal failure.PKD1 mutations cause 85% of ADPKD. Feline PKD is autosomal dominantand has clinical presentations similar to humans. PKD affects38% of Persian cats worldwide, which is 6% of cats, making itthe most prominent inherited feline disease. Previous analyseshave shown significant linkage between the PKD phenotype andmicrosatellite markers linked to the feline homolog for PKD1.In this report, the feline PKD1 gene was scanned for causativemutations and a C>A transversion was identified at c.10063(human ref NM_000296) in exon 29, resulting in a stop mutationat position 3284, which suggests a loss of 25% of the C-terminusof the protein. The same mutation has not been identified inhumans, although similar regions of the protein are truncated.The C>A transversion has been identified in the heterozygousstate in 48 affected cats examined, including 41 Persians, aSiamese, and several other breeds that have been known to outcrosswith Persians. In addition, the mutation is segregating concordantlyin all available PKD families. No unaffected cats have beenidentified with the mutation. No homozygous cats have been identified,supporting the suggestion that the mutation is embryonic lethal.These data suggest that the stop mutation causes feline PKD,providing a test to identify cats that will develop PKD anddemonstrating that the domestic cat is an ideal model for humanPKD.
Companion animal species such as the domestic cat are effectivemodels for several inherited diseases. Cats and humans showstrong conservation of biology and anatomy and share >30homologous hereditary diseases (1,2). One inherited diseasefor which the cat is an exceptional animal model is polycystickidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is a commonlyinherited disorder in humans, with a frequency in the generalpopulation of 1 in 1000 (3). Approximately 85% of ADPKD casesare caused by mutations in the PKD1 gene (4,5), located on humanchromosome 16p13.3; the remaining 15% are caused by mutationsin the PKD2 gene, located on human chromosome 4q21–23(6,7). ADPKD is characterized by the formation of fluid-filledcysts in the kidneys, and the average age of onset is 40 yr,with ESRD occurring by age 60 in 50% of cases (8). This suggeststhat 4% of ESRD patients are a result of PKD.
Feline polycystic kidney disease is an inherited disease inPersian and Persian-related cats. PKD in cats is characterizedby renal as well as hepatic and pancreatic cysts (9) and hasan autosomal dominant mode of inheritance (10,11). Approximately38% of Persian cats in the United States (12) and worldwide(13–17) are positive for PKD. Purebred cats represent20% of the cat population in the United States, and Persian-typebreeds constitute 80% of the cat fancy; hence, PKD is the mostprominent inherited feline disease.
A linkage analysis for feline PKD was performed by genotyping43 feline-derived microsatellites in seven extended feline pedigreessegregating for PKD (18). The results showed a significant linkageand no recombinants (Z = 5.83, = 0) between feline PKD andthe microsatellite marker FCA476 that is within 10 cR to thePKD1 gene on cat chromosome E3 (18).
A BAC clone that contains the feline PKD1 gene was identifiedand submitted for sequencing at The University of Oklahoma’sAdvanced Center for Genome Technology. PCR amplification andsequence analysis identified a C>A transversion causing astop codon (OPA) in exon 29 of the feline PKD1 gene. This mutationhas been identified in the heterozygous state in all 48 affectedcats examined to date, including all affected Persians, a Siamese,Ragdolls, domestic shorthairs, and several other breeds thathave been known to outcross with Persians, such as Exotic Shorthair,Selkirk Rex, and Scottish Folds. The mutation is segregatingconsistently in the largest feline PKD pedigree and in severalindividuals from all other available pedigrees. The causativemutation has not been observed in 33 unaffected cats, and nohomozygous affected cats have been identified, suggesting thatthe mutation is embryonic lethal and is consistent with previousdata (18). These data suggest that the stop mutation causesfeline PKD and that a DNA test is now possible to identify catsthat will develop PKD in the future. Along with the similarclinical presentation, these data support the use of the domesticcat as a model for human PKD. The cat has the same mode of inheritance,a mutation in the PKD1 gene; the affected cats have only theheterozygous state, and they can be used for long-term drugand potentially gene therapy trials.
All animal experimentation described in this article was conductedin accord with the National Institutes of Health Guide for theCare and Use of Laboratory Animals.
Sample Identification
Samples from cats that represent families segregating with PKDwere collected from five feline PKD ultrasound screening clinicsthat were held at the University of California, Davis, Schoolof Veterinary Medicine between June 2000 and September 2002.Cats of 10 mo of age or older were determined to be affectedor normal by the visualization of singular bilateral or multipleunilateral cysts using ultrasonography. The same two board-certifiedradiologists (D.A.B. and Dr. E. Herrgesell of the Universityof California, Davis, School of Veterinary Medicine) scannedall cats. Details regarding the disease criteria and the pedigreesdeveloped from these clinics have been previously described(18). Forty-eight affected and 33 normal cats were analyzed.Representatives from each pedigree were genotyped for the PKDmutation, including 41 affected and 26 unaffected Persians.One PKD-affected cat and one normal cat from other breeds, includingSiamese, Siberian, Exotic Shorthair, Domestic Shorthair, SelkirkRexes, Scottish Folds, and Ragdolls, were identified by theauthors (D.J.B.) and/or from the University of California, Davis,ultrasound screening clinics and were also analyzed.
BAC Clone Sequencing
The sequence of the feline BAC clone (GenBank accession no.AC145332.26) that contains the feline PKD1 homolog was obtainedusing standard BAC isolation, shotgun sequencing, and finishingstrategies as described previously (19–23). Primers fromexon 17 that had an 8-bp overlap in the 3' portion of theirsequence were constructed. Thus, when amplified, they produceda product of 40 bp that was used as a probe to isolate the BACclone that contains the feline PKD1 gene. Commonly termed "overgo"primers, the sequences for these primers were PKD1F tgcccattgtgtccttggagtgtgand PKD1R tgtgccttgcaggacacacactcc. Briefly, 50 µg ofpurified BAC DNA was randomly sheared and made blunt-ended.After kinase treatment and gel purification, fragments in the1 to 3 kb range were ligated into SmaI-cut, bacterial alkalinephosphatase (BAP)-treated pUC18 (Pharmacia) and transformedby electroporation into Escherichia coli, strain XL1BlueMRF’(Stratagene, La Jolla, CA). A random library of 2500 colonieswere picked from the transformation and grown in Terrific Broth(TB) medium supplemented with 100 µg of ampicillin for14 h at 37°C with shaking at 250 rpm, and the sequencingtemplates were isolated by a cleared lysate-based protocol.Sequencing reactions were performed as described previouslyusing TaqDNA polymerase with the Amersham ET Fluorescence-labeledterminators (19–22). The reactions were incubated for60 cycles in a Perkin-Elmer Cetus DNA Thermocycler 9600, andafter removal of unincorporated dye terminators by ethanol precipitation,the fluorescence-labeled nested fragment sets were resolvedby electrophoresis on an ABI 3700 Capillary DNA Sequencer. Theresulting sequence data were transferred to a Sun WorkstationCluster, where it was base-called and assembled using the Phredand Phrap programs (24,25). Overlapping sequences and contigswere analyzed using Consed (26).
Fluorescence in situ hybridization (FISH) of the PKD1 BAC clonewas performed on mitotic spreads of feline chromosomes usingstandard methods. Labeling procedures and probe concentrationswere the same as described previously (27). Cot-1 DNA was substitutedin the hybridization solution with a twofold amount of cat genomicDNA.
PKD1 Sequence Analysis
Sequence of the PKD1-containing BAC clone (GenBank accessionno. AC145332.26) was aligned to the human (GenBank accessionno. AC009065.8), dog (GenBank accession no. AY102170.1), andmouse (GenBank accession no. AC132367.3) PKD1 sequences to identifypotential intron/exon boundaries for the cat using the softwarePipMaker (28) (Figure 1). Primers were developed in intronicregions for amplification of complete exons using the softwarePrimer3 (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi)(29) and NetPrimer (http://www.premierbiosoft.com/netprimer/netprlaunch/netprlaunch.html).Primers and the GenBank accession numbers for the exons analyzedare presented in Table 1. Primers (MWG Biotech, High Point,NC) were used to amplify PKD-negative control cat DNA. Eachprimer was tested in the cat as described previously (30) ona Stratagene 96-well temperature gradient Robocycler. The amplifiedproducts were separated on 1.8% agarose gels at 100 Vhr. Gelswere visualized by UV exposure after ethidium bromide stainingand photodocumented using the Alpha Imaging System (Alpha Innotech,San Leandro, CA). A positive optimization of the primers produceda single PCR product that was excised from the gel and purifiedusing the Qiagen gel extraction column (Qiagen, Valencia, CA),or PCR products were purified directly using the Qiagen PCRclean up kit. Purified products were sequenced directly in bothdirections using the ABI Dye Terminator Sequencing chemistryv3.1 (Applied Biosystems, Foster City, CA). Sequencing reactionswere separated on an ABI 377 DNA Analyzer, and the DNA contigsequence was assembled using the Sequencer Software package(Gene Codes, Ann Arbor, MI). Integrity of the sequence contigwas confirmed by visual inspection and verified to be the correctgene by comparison with sequences in GenBank using BLAST (31).
Figure 1. Schematic diagram of the feline PKD1 gene as suggested from the BAC clone sequence. Intron/exon boundaries are predicted by comparison with human, mouse, and dog sequence as determined with the program PipMaker (28). The y axis represents nucleotide identity of the cat to the human sequence, and the x axis represents nucleotide position in the gene. The exon number is represented above each exon symbol. , simple repeat; , UTR; , exon; , gene;, CpG/GpC0.75; , CpG/GpC0.60.
Genotyping
DNA from 48 affected and 33 normal cats was isolated from whitecells by standard phenol/chloroform techniques. EDTA anticoagulatedblood was collected by venipuncture at the PKD clinics or sentby private clinicians. PKD exon products were amplified by PCRfrom genomic DNA of two normal and two affected cats using theoptimized primers (Table 1). Individual exons were amplifiedindependently in feline DNA samples using optimal PCR conditionson a Stratagene 96-well temperature gradient Robocycler. Approximately12.5 ng of DNA was used per PCR reaction. Reaction conditionsfor each primer pair were as follows: 1 pmol of each forwardand reverse primer, 1.25 mM dNTP, 1.75 mM MgCl2, 1x PCR bufferII, and 0.375U of Amplitaq (Applied Biosystems) polymerase in10 µl reaction volumes. Cycling parameters included aninitial 3 min denaturation at 94°C followed by 35 cyclesof 1 min denaturation at 94°C, annealing for 1 min at 58°C,and a 72°C extension for 1 min. The cycling parameters werefollowed by a final extension at 72°C for 10 min. Productswere generated, visualized, gel-extracted, purified, and sequencedas described above and analyzed for mutations associated withPKD. Sequences generated from each exon were aligned (DNAStar,Madison, WI) with wild-type cat sequence to identify possiblecausative mutations for the observed phenotype. When polymorphismswere detected, sequence data were translated to determine whetherthe mutation resulted in an amino acid change.
RFLP Analysis
Once the mutation was identified, 46 affected and 31 normalcats were screened for the PKD mutation using RFLP typing onagarose gels. The amplification product for exon 29 is 559 bp.The identified mutation causes a restriction enzyme site alterationfor MLY1, producing two fragments of 316 and 243 bp. Approximately5 µl of amplification product was digested with 10 U ofMLY1 (New England Biolabs, Beverly, MA) in a 10 µl reactionthat contained 1x NE Buffer 4 at 37°C for 3 h followed byinactivation of the enzyme at 65°C for 10 min. The completedigestion reaction was analyzed on 1.8 to 2% agarose gels asdescribed above.
The sequenced BAC clone (GenBank accession no. AC145332.26)is in eight contigs that cover 167 kb. The region that containsthe PKD1 gene is represented by two contigs that are separatedin intron 4. The 5' region of exon 1 is not complete, with anestimated 278 bp not represented in the assembled sequence.A schematic of the feline PKD1 gene is presented in Figure 1,which predicts exon sizes in the genomic BAC clone and sequenceidentity to the annotated human mRNA sequence. Intron and exonsizes as well as estimates of sequence and protein identityto human, mouse, and dog are presented in Table 2. Over allexons, the cat sequence is most similar to dog (83.66%; range,75.0 to 94.4%), least similar to mouse (73.44%; range, 45.3to 89.6%), and intermediately similar to humans (80.02%; range,64.9 to 94.4%). Exon 10 has the lowest similarity with the catas compared with each species. The similarity of cat sequenceto that from any second species (mouse, human, or dog) variesbetween exons. One would expect the cat always to be most similarto the dog, a fellow carnivore, but this was not the case. Thepredicted mRNA and protein sequence is provided in a Supplementalfigure. FISH of the PKD1 BAC clone does not suggest duplicationof the feline PKD1 gene (Figure 2), and the feline gene is locatedon cat chromosome E3. Nine of 46 PKD1 exons were scanned formutations by direct sequencing. A C>A transversion at c.10063(human ref NM_000296) in exon 29 resulting in a C3284X proteinchange was identified, which is an OPA stop codon that shouldcause a loss of 25% of the protein (Figure 3). The mutationcauses a unique RFLP site in the amplification product of exon29. An example of the RFLP typing is presented in Figure 4.A total of 48 affected and 33 unaffected cats were scanned forthis stop mutation. Ten cats were confirmed by sequence analysesand all cats by RFLP. All 48 affected cats had the stop mutation,including the non-Persian cats. None of the 33 unaffected catswas identified with the mutation. Pedigree analysis of felinePKD family 5 (18) showed complete co-segregation of the stopmutation with the disease phenotype. None of the 48 affectedcats was found to be homozygous for the mutation.
Figure 2. Localization of the feline PKD1 gene by fluorescence in situ hybridization to domestic cat chromosome E3q13. Presented is a mitotic spread of feline chromosomes from lymphocytes with the hybridization of the feline PKD1 BAC clone (a; arrows). Hybridization signals are observed as red dots on both E3 chromosomes. Each dot represents the signal of a single chromatid. (b) The inverted DAPI-banding pattern of the same metaphase. Feline chromosome E3 is the smallest metacentric cat chromosome and is easily distinguished by its morphology and DAPI-banding pattern.
Figure 3. (a) DNA alignment of PKD1 exon 29 from mouse, human, dog, and cat. Both wild-type and mutant sequences are included from the cat. Boldface in cat sequence indicates the transversion observed in polycystic kidney disease (PKD)-affected cats causing a change in the amino acid translation resulting in an OPA stop codon. (b) Protein alignment of PKD1 exon 29 from mouse, human, dog, and cat. Both wild-type and mutant translations are included from the cat. Boldface X in the cat sequence indicates the OPA stop codon observed in PKD-affected cats.
Figure 4. RFLP typing for the feline PKD mutation. Amplification products of exon 29 were digested with the restriction enzyme MLY1. The 559-bp product is digested into two fragments of 316 and 243 bp. All cats affected with PKD produced the wild-type 559-bp fragment and the digested fragments. A 1-kb+ marker is in lanes A and F. Lanes B and E are unaffected cats, and lanes C and D are affected cats.
Four of the nine exons (exons 6, 14, 15, 23, 24, 29, 30, 37,38) and several intron regions had nucleotide variants as identifiedbetween two sequenced Persian cats and the PKD1 sequence fromthe BAC clone (Table 1). One Persian was affected with PKD;thus, the sequence comparison represents three normal alleles.Each identified variant was homozygous in the two Persian cats,except for a mutation in exon 29. Ten variants were identified,but only four were in translated regions of the exons. Nonewas identified at exon/intron splice sites. Two of the fourvariants produced silent mutations and were homozygous in thetwo Persian cats sequenced. One mutation, a C>T transitionat position 127 of exon 38, caused an amino acid change, butboth amino acids are hydrophobic and it is not anticipated thatthis substitution alters the protein conformation. One primerset amplified exons 21 and 22 and the intervening intron 21,and another set amplified exons 22 and 23 and the interveningintron 22 (Table 1). Both cat introns are shorter than the correspondinghuman intron (Table 2), and no sequence data from the BAC cloneand/or amplified genomic DNA supported the presence of polypyrimidinetracts.
Domestic cats are effective models for several inherited diseasesand should be used to develop better drug and gene therapiesfor PKD. Feline PKD is an inherited disease in Persian and Persian-relatedcats. As with humans, PKD in cats is characterized by renalas well as hepatic and pancreatic cysts (9) and has an autosomaldominant mode of inheritance (10). Approximately 37% of Persiancats worldwide (14) are PKD affected. Only 20% of the cat populationin the United States is represented by purebred cats, but ofpurebreds, Persians and Persian-derived breeds constitute 80%of the cat fancy (32). This suggests that 6% of the cat populationin the United States has PKD, making it the most prominent inheritedfeline disease.
Our previous linkage analyses strongly implicated PKD1 as thecausative gene for feline PKD (18). Each newly identified familyfor human PKD has generally been found to be a novel mutationin the PKD1 gene. Mutations are found throughout the gene, withno single mutation being highly prevalent in the population.Because no particular mutation or region of the PKD1 gene inhumans is highly prevalent for mutations, identification ofthe feline PKD mutation could have entailed the complete sequencingof the feline homolog from an affected cat. Once the draft sequenceof the feline BAC clone containing PKD1 was obtained, we begana systematic scan for mutations. A nucleotide transversion causinga stop codon was identified in exon 29 that suggests a truncationof the protein with a loss of 25% of its C-terminus. Thus, thisfeature is a very strong candidate for the causative mutationresulting in the PKD phenotype.
In addition, concordant segregation of the mutation with thedisease in a large cat family segregating for PKD supports thestop mutation as causative for feline PKD. A different mutationstill possibly could cause feline PKD but would have to be instrong linkage disequilibrium with this stop codon. In addition,the stop codon mutation is consistent with the microsatellitehaplotype that shows complete linkage to the PKD phenotype (datanot shown).
The feline PKD1 gene is represented by two contigs, with the5' region of exon 1 and intron 4 not yet represented by sequence.A majority of feline exon and intron sizes are estimated fromthe BAC clone sequence. In humans, exon 1 is 424 bp; thus, 141amino acids cannot be compared with the cat. Intron 4 is 213bp in humans, and this entire intron may not yet be representedin the cat sequence. Over all exons, the cat sequence is mostsimilar to dog, followed by human, and least similar to mouse,which is consistent with the evolutionary relationship of thespecies. Exon 10 is the least similar for all species, as comparedwith the cat.
There are two distinctive features found in the human PKD1 genethat distinguish it from the homolog in mice and dogs (33–36):(1) the presence of polypyrimidine tracts in intron 21 (2.5kb) and intron 22 (600 bp) and (2) the presence of several replicatesof a 13.5-kb region of the 5' portion of the gene on human chromosome16. Neither feature is present in the cat. The genomic amplificationsof introns 21 and 22 from both normal and affected cats areconsistent with the size determined by the feline BAC clonesequencing. Introns 21 and 22 both are smaller in cats thanin humans. When human-derived primers were used to amplify aregion that consisted of a majority of exon 21, exon 22, andthe intervening intron 21, this region is 950 bp in cats andcould not be amplified from genomic human DNA, suggesting thatthe 2.5-kb tract could not be amplified by standard PCR. Thepolypyrimidine tract is not represented in the human referencesequence for PKD1 but has been demonstrated elsewhere and confirmedby long-PCR techniques (34). Intron 22 is only 349 bp as comparedwith 602 bp in humans. Thus, the polypyrimidine features arenot found in cats.
Likewise, three aspects of our data suggest that the 5' portionof the feline PKD1 gene homolog is not replicated as in humans.For the cats sequenced, heterozygous sequence was not identifiedwithin the exons and introns that correspond to the region duplicatedin humans. Pseudogenes acquire mutations rapidly; thus, it wouldbe anticipated that some variants would be detected. FISH ofthe PKD1 BAC clone does not suggest duplication and was locatedon feline chromosome E3, which is as predicted by genetic mapping(37) and chromosome painting (38) and is the region homologousto human chromosome 16. In addition, because this region isnot replicated in both mice and dogs, it is more likely thatthis replication event is found in humans and/or primates andis not an ancestral event for mammals.
Only the Persian and Persian-derived cat breeds (Exotic Shorthairsand Himalayans) have been recognized to have a high frequencyof PKD. Other breeds—Ragdolls, Scottish Folds, and SelkirkRexes—have either purposely or accidentally bred to Persians.We hypothesize the PKD mutation in the other breeds to be identicalby descent with the Persian mutation. All affected cats fromthe other breeds have the identical mutation as the Persians.Because a majority of human cases are de novo, more extensivesequence analyses are required to differentiate de novo, identicalby state mutations from mutations that are identical by descentwithin various cat breeds. This disease is occurring withina closed breed, suggesting that identity by descent and diseasehomogeneity is expected. Persians, however, are one of the oldestand most popular breeds, having a large population that is dispersedthroughout the world. All cases analyzed here represent catsfrom the United States; thus, more extensive surveys shouldbe conducted to validate the causative mutation in differentregions of the world.
Further investigation into the cause of PKD will be valuablefor feline health as well as provide insights into human ADPKD.As with humans, cats have a wide range of disease progressionand severity; thus, other genetic and environmental factorscould influence disease progression (39–42). Currently,the disease is highly prevalent in the cat population, makingthe identification of both severe, early-onset cases and mild,late-onset cases feasible. This could lead to the identificationof genetic modifiers. As cats have similar clinical presentations,therapies that are under development for epidermal growth factorreceptor (EGFR) could be tested for efficacy in the cat, beforeuse in humans (43–47).
Persian and Persian-related cats should be screened for PKDby ultrasound before they are bred (47). Although breeders areadvised not to breed two positive cats, they are often bredfor several unrelated reasons: (1) clinical signs have not yetappeared; (2) many breeders are still unaware of the disease;(3) ultrasound is either unavailable or cost-prohibitive; (4)breeding decisions are made before adequate accuracy of diagnosis;and (5) the disease is highly prevalent; thus, many catteriescould lose 40% of their breeding population. A genetic testfor feline PKD will provide breeders with an efficient and accuratemeans to selectively breed their cats and remove PKD from thepopulation. Because PKD has been found in other cat breeds relatedto Persians, the incidence of PKD in these breeds should beevaluated.
Acknowledgments
Funding has been provided to L.A.L. by the Winn Feline Foundation,the Waltham Foundation, and the George and Phyllis Miller FelineHealth Fund, Center for Companion Animal Health, School of VeterinaryMedicine, University of California, Davis, and to B.A.R. fromNational Institutes of Health, National Human Genome ResearchInstitute Grant HG002153.
We are grateful to the cat breeders who participated in thePKD screening clinics and provided samples for analysis andthe FISH data from Dr. Lutz Froenicke. Patent pending: UC CaseNo. 2004-447.
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Received for publication May 5, 2004.
Accepted for publication July 18, 2004.
This article has been cited by other articles:
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Genome Res.,
November 1, 2007;
17(11):
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[Abstract][Full Text][PDF]
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Abstract
Introduction
38% of Persian cats worldwide, which is 
= 0) between feline PKD and the microsatellite marker FCA476 that is within 10 cR to the PKD1 gene on cat chromosome E3 (18). 
, simple repeat; 
, UTR; 
, exon; 
0.75; , CpG/GpC
