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Human Molecular Genetics Pages 509-513  

Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease
Introduction
Results And Discussion
Materials And Methods
   Patient information
   Isolation of cyst epithelial cells and genomic DNA extraction
   Search for LOH
   SSCP, heteroduplex analysis and DNA sequencing
Acknowledgements
References

Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease

Germinal and somatic mutations in the PKD2 gene of renal cysts in autosomal dominant polycystic kidney disease

Michael Koptides1, Christos Hadjimichael1, Panayiota Koupepidou1, Alkis Pierides2 and C. Constantinou Deltas1,*

1The Cyprus Institute of Neurology and Genetics, Department of Molecular Genetics and 2Department of Nephrology, Nicosia General Hospital, Nicosia, Cyprus

Received November 4, 1998; Revised and Accepted December 10, 1998

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in one of three genes: PKD1 on chromosome 16 accounts for ~85% of cases whereas PKD2 on chromosome 4 accounts for ~15%. Mutations in the PKD3 gene are rare. All patients present with similar clinical phenotypes, and the cardinal symptom is the formation of fluid-filled cysts in the kidneys. Previous work has provided data supporting the notion that cysts in ADPKD1 are focal in nature and form after loss of function of polycystin 1. This became evident by demonstrating that the normal PKD1 allele was inactivated somatically by loss of heterozygosity or by mutagenesis in a subset of renal or liver cysts examined. We show in this report, for the first time, multiple novel somatic mutations within the PKD2 gene of epithelial cells, in both kidneys of an ADPKD2 patient. From a total of 21 cysts examined, seven (33%) had the same C insertion within the inherited wild-type allele. In two other cysts, a nonsense mutation and a splice site AG deletion had occurred in a PKD2 allele that could not be identified as the inherited wild-type or mutant. We suggest that the autosomal dominant form of ADPKD2 occurs by a cellular recessive mechanism, supporting a two-hit model for cyst formation.

INTRODUCTION

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic inherited disorders with an approximate frequency of 1:1000 individuals (1). The PKD1 and PKD2 genes on chromosomes 16p13.3 and 4q13-23, respectively, have been cloned and sequenced, and many mutations of various types have been characterized (2-5). The gene products, polycystins 1 and 2, are speculated to be part of a common developmental pathway that involves cell-cell and cell-matrix interactions, leading to the transfer of signals into the intracellular milieu. According to a proposed model, the 968 amino acid polycystin 2 is an integral membrane protein with six transmembrane domains and intracytoplasmic N- and C-termini, sharing homology with 270 residues of a voltage-activated calcium channel (3). Recent data have suggested that the products of the PKD1 and PKD2 genes, polycystin 1 and polycystin 2, respectively, interact through their cytoplasmic C-terminal domains (6,7). One striking characteristic of ADPKD is that although all epithelial renal cells bear the same inherited germinal mutation, only a small fraction of nephrons become cystic. The hypothesis that a second hit may be required and necessary for cyst formation and disease development was supported by work on ADPKD1 which demonstrated loss of heterozygosity (LOH) and somatic mutations in DNA from renal cystic epithelial and liver cells. In all cases, the wild-type PKD1 allele was lost (8-10) or had mutated (11). Based on the similarity of phenotypes, it was assumed that the same hypothesis may hold true for the underlying mechanism leading to cyst formation in ADPKD2 patients. Wu et al. (12) showed very elegantly in a murine model that cyst formation is the result of somatic inactivation of both Pkd2 alleles.

In this work, we show directly for the first time the presence of somatic inactivating mutations in the inherited normal allele of PKD2, in the cysts of both kidneys of an ADPKD2 patient. Interestingly, the same somatic defect was present in DNA from seven different cysts.

RESULTS AND DISCUSSION

The main feature of ADPKD pathology is the formation and development of cysts in many organs, primarily the kidneys and secondarily the liver and pancreas. However, only a small fraction of renal cells become cystic. Initially, the proposed hypothesis stated that a second hit may be needed after fetus conception, which would trigger cyst formation (13). We investigated this hypothesis by obtaining both kidneys post-mortem of an ADPKD2 patient belonging to a family where the pathogenic germinal mutation is the insertion of a cytosine residue after Leu231 in exon 2 (693insC; nucleotide number 1 is the A of the first methionine codon) (14). We isolated DNA from epithelial cells of the inner wall of well-separated individual cysts and searched for LOH. Based on the evidence that the polycystin 1 and 2 proteins structurally interact with one another (6,7), we examined the genotypes of DNA polymorphic markers in and around both PKD1 and PKD2 loci. We did not detect LOH for either gene (data not shown). Subsequently, we investigated the hypothesis that the inherited wild-type PKD2 allele may have been inactivated through somatic mutagenesis. For this, the entire coding region of the gene was examined by single strand conformational polymorphism (SSCP) and part of the gene by heteroduplex analysis. Heteroduplex analysis failed to identify any abnormal patterns, except for finding the known mutation in exon 2 (14). However, screening by SSCP revealed aberrant electrophoretic migration of PCR-amplified products in three different exons.

A new molecular species detected by SSCP around exon 4 from cyst C7 DNA was sequenced directly from PCR products. Sequencing in both directions revealed the presence of a stop codon that substituted arginine 327 (R327X) (Fig. 1A). The nucleotide substitution was a transversion of adenosine to thymidine at the first position of the codon (AGA->TGA). It was impossible to determine whether this potentially deleterious mutation had occurred in the inherited mutant or the wild-type allele. A second SSCP variant around exon 10 from cyst C19 DNA could not be elucidated by direct sequencing of PCR products. Thus, subsequent cloning of these fragments and sequencing of multiple clones revealed a de novo deletion of the conserved AG dinucleotide at the 3[prime] splice site in intron 9 (Fig. 1B). This mutation, denoted as 2020-2delAG, is expected to result in aberrant splicing and perhaps deletion of exon 10 or inclusion of intron 9, if no cryptic splice sites are activated. As for the previous mutation, it is not known in which allele this deletion had occurred.


Figure 1. Demonstration of mutations R327X (nucleotide 979 A->T) (A) and 2020-2delAG (B) in the PKD2 gene. DNA isolated from epithelial cells in the inner cyst wall of cysts C7 and C19 was analysed initially by SSCP. (A) Direct forward sequencing of the PCR product around exon 4 revealed a co-migration of A with T, resulting in a substitution of a stop codon for Arg327. Left panel, DNA from cyst C7; right panel, DNA from the patient’s leukocytes. (B) Direct sequencing of PCR products around exon 10 was equivocal; therefore, the DNA products of four independent PCR amplifications were cloned as described in Materials and Methods and many clones were sequenced. Seven out of 17 clones had a deletion of the conserved AG dinucleotide at the 3[prime] splice site (acceptor) in intron 9. Left panel, a representative clone with the deleted AG dinucleotide. Shown is the reverse sequence with the deleted TC nucleotides denoted by asterisks. Right panel, a representative clone with normal reverse sequence. Samples were run on a 6% denaturing polyacrylamide gel, without formamide.


Figure 2. Sequencing of clones around the regions of interest showing the cystic somatic mutation 197-203insC, and the nearby polymorphism, R28P, which permitted the discrimination of alleles. Forward and reverse sequencing in the presence of dITP as a dGTP analogue and inclusion of 40% formamide within the denaturing sequencing gels were necessary for resolving misleading compressions and artefacts, caused by the high GC content of the region. (A) Forward sequencing of DNA from cyst C6 (alleles 1 and 2) and of DNA isolated from the patient’s leukocytes (allele 3), showing the region around polymorphic nucleotide 83. (B) Reverse sequencing of the same samples as in (A), showing the region around the somatic mutation. The newly introduced G in the antisense strand (allele 1) was inserted somewhere between the shown arrows. In (A) and (B), allele 1 on the left represents that arising from the somatic de novo insertion of a C between residues 197 and 203, and which occurred on the inherited wild-type allele with G at position 83. Allele 2 represents the inherited mutant with a C at position 83, and allele 3 represents the inherited wild-type allele with G at position 83. (C) Schematic representation of the three PKD2 alleles found in the DNA isolated from the patient’s leukocytes and/or from epithelial cells of the renal cysts. The polymorphic nucleotides at position 83 are underlined. Also underlined is the newly introduced C in the allele with a germinal mutation after amino acid 231 (nucleotide 693). In leukocytes, alleles 2 and 3 are present, whereas in the DNA of seven cysts, alleles 1 and 2 are present. aa, amino acid; nt, nucleotide.

Another more startling finding was within exon 1 of seven cysts, three from the left kidney and four from the right (Fig. 2). All seven cysts shared the same SSCP variant, and direct sequencing of PCR products showed the insertion of a new cytosine within a series of six consecutive cytosines (nucleotides 197-203), encoding amino acids 66-68, denoted as 197-203insC. It is impossible to determine exactly where the insertion of the cytosine occurred. However, it is expected to create a translation frameshift which would lead to incorporation of 22 novel amino acids before it reaches a stop codon. Fortuitously, we identified a nearby polymorphism at position 83, which was occupied by either G or C, encoding either arginine or proline (R28P). This polymorphism enabled us to verify that the disease was co-inherited with allele C (Fig. 3). Cloning and sequencing of cystic DNA showed that the C insertion at position 197-203 had occurred in the inherited wild-type allele, thereby rendering cystic cells devoid of normal polycystin 2 (Fig. 2).


Figure 3. Demonstration of inheritance of polymorphism R28P in ADPKD2, as represented by nucleotide G or C at position 83 (arginine or proline). The C allele is associated with a recognition site for the restriction enzyme Bsp1286I (asterisk). All affected members in the family share the C allele. Although some married-in individuals also have the C allele, the inheritance pattern shows clearly that the C allele is the one affected with the germinal mutation 693insC (14). The PCR-amplified DNA samples were digested and electrophoresed on a 2% NuSieve 3:1 agarose gel. The small 9 bp fragment ran off the gel. Lane M on the right contains a 100 bp molecular weight marker.

The recurrent occurrence of this last mutation, 197-203insC, in one-third of the cysts examined, suggests that this position may represent a mutational hotspot. The insertion took place within the only sequence of six consecutive cytosines of the PKD2 coding region, something that is known to be particularly prone to mispairing due to strand slippage. In addition, the entire exon 1 sequence is 77.5% GC rich, something that may also render it prone to mutations. The finding of two variants in such a small part of exon 1, namely the insertion 197-203insC and the polymorphism R28P, may be indicative of high mutagenicity, a finding also established for the PKD1 gene. In fact, the increased mutagenicity may partly explain the high incidence of cyst formation in both ADPKD1 and ADPKD2 kidneys, and the formation of simple cysts during ageing (1). Also, polymorphism R28P, with two very dissimilar amino acids occupying the same position near the N-terminal end of polycystin 2, perhaps suggests a less important role for this part of the protein.

It is not known whether the somatic mutations preceded the development of cysts, or followed their hyperproliferation (15,16). Perhaps there is still a need for a more direct demonstration of a cause-and-effect relationship between somatic mutations and cyst formation. Nevertheless, in the light of recent experiments (12), our findings support the two-hit hypothesis for cyst formation in ADPKD2. Wu et al. had shown that the development of polycystic kidney disease in a murine model was the result of intragenic homologous recombination that led to somatic inactivation of both PKD2 genes, thereby suggesting that ADPKD2 occurs by a cellular recessive mechanism (12). If the de novo insertion of the C in seven of the cysts examined in this work had happened after cyst formation, and was not causative of cystogenesis, one would expect it to have happened with equal frequency on both alleles. However, this was not the case, since in all seven cysts the C insertion was found only in the germinal wild-type copy allele.

Somatic mutagenesis as the triggering event of cyst formation and disease development would account for the great intra- and interfamilial phenotypic variation which clearly characterizes ADPKD (1). It would also account for the age-dependent penetrance, since the somatic mutations would happen as stochastic events triggered by endogenous or environmental factors any time during intra- and extrauterine life.

It did not escape our attention that only nine of 21 (43%) of the cysts examined showed somatic mutations. This may be due to various reasons, the most probable of which pertains to the inherent weakness of the SSCP approach we used for mutation detection. SSCP does not identify 100% of single nucleotide variants, whereas small or larger deletions around the PCR primer recognition sequence would lead to hemizygosity. Also, potential mutations in the rest of the intronic sequences would be missed since we only focused on the exonic regions and the exon-intron boundaries.

In conclusion, we have presented for the first time direct evidence supporting the two-hit hypothesis, according to which aberrant cyst formation in ADPKD2 kidneys is the result of inactivation of both PKD2 genes in renal epithelial cells. One mutant gene is inherited and the second gene is inactivated through somatic second hits represented by de novo mutations in certain hotspots or elsewhere in the gene. This is certainly a finding that follows the Knudson’s two-hit model for carcinogenesis (17), and provides molecular support for the previous characterization of fluid-filled cysts as ‘neoplasia in disguise’ (18).

MATERIALS AND METHODS

Patient information

The patient belongs to a family, CY1602, that was investigated previously by DNA linkage analysis (19) and had shown clear evidence for linkage to the PKD2 locus on chromosome 4. The pathogenic mutation subsequently was shown to be an insertion of C after leucine 231 in exon two (693insC) (14). At the age of 54 years, the patient had a mild cerebrovascular accident, and at 64 years he presented with hypertension. He reached end-stage renal disease and commenced haemodialysis at the age of 70 years. He died at age 79 years, at which time both kidneys were removed on informed consent by the relatives.

Isolation of cyst epithelial cells and genomic DNA extraction

In both kidneys there were hundreds of cysts of variable size. The isolation of cystic epithelial cells and DNA extraction were performed as described previously for ADPKD1 kidneys (9,10), exercising caution to avoid non-cystic cells. This involved rinsing the inner surface of cystic slices in excess phosphate-buffered saline (PBS) and scraping it with a surgical blade, whilst keeping the cyst outer wall intact. Epithelial cells were obtained from 21 individual well-separated cysts, eight from the left and 13 from the right kidney.

Search for LOH

LOH around the PKD1 and PKD2 loci on chromosomes 16 and 4, respectively, was investigated with the use of intragenic and flanking markers as described previously (10). Since the inherited mutation in the patient was known, 693insC in exon 2, LOH was investigated easily by PCR amplification and heteroduplex analysis as previously shown (14). The co-amplification of the normal and the mutant allele gives a unique pattern by heteroduplex analysis. The proximal flanking marker D4S231 was also used for this purpose. For investigation of LOH in and around PKD1, the intragenic markers KG8 and IVS42 were used, as well as flanking markers HBAP1, SM6 and 16AC2.5. Unfortunately, KG8 and IVS42 were not informative.

SSCP, heteroduplex analysis and DNA sequencing

The entire PKD2 gene, which is encoded in 15 exons, was screened for mutations using an exon-by-exon approach. Fourteen pairs of primers located in the flanking sequence of exons 2-15 and three pairs covering the first exon were used for mutation screening, using DNA from 21 cysts as templates, as described previously (14). The entire collection of primers used is described elsewhere (20). Exons showing aberrant SSCP patterns were either sequenced directly using the PCR sequencing kit from USB (Amersham, Cleveland, OH) according to the manufacturer’s instructions, or were sequenced after cloning into the pPCR-Script SK(+) vector (Stratagene, La Jolla, CA). Recombinant clones represented by white colonies were easily screened for the two polymorphic alleles exploiting a restriction enzyme recognition site around the polymorphic nucleotide 83. The C allele creates a recognition site for Bsp1286I.

For all PCR amplifications, extreme precaution was exercised to avoid carry over or external DNA contaminations. Preparation of samples was within a specially used self-contained compartment (Template Tamer; Coy, MI), and blank samples containing everything but DNA were included in all series of amplifications.

ACKNOWLEDGEMENTS

We wish to thank the relatives of the patient for their co-operation in this study, and Dr I. Zouvani for assisting us in obtaining the ADPKD kidneys post-mortem. This work was funded by the Cyprus Ministry of Health, the Telethon 97 and a grant from the Cyprus Kidney Association to C.C.D.

REFERENCES

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2. European Polycystic Kidney Disease Consortium (1994) The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell, 77, 881-894. MEDLINE Abstract

3. Mochizuki, T., Wu, G., Hayashi, T., Xenophontos, S., Veldhuisen, B., Saris, J.J., Reynolds, D., Cai, Y., Gabow, P., Pierides, A., Kimberling, W., Breuning, M., Constantinou Deltas, C., Peters, D. and Somlo, S. (1996) PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science, 272, 1339-1342. MEDLINE Abstract

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5. Veldhuisen, B., Saris, J.J., De Haij, S., Hayashi, T., Reynolds, D.M., Mochizuki, T., Elles, R., Fossdal, R., Bogdanova, N., van Dijk, A.M., Coto, E., Ravine, D., Norby, S., Verellen-Dumoulin, C., Breuning, M.H., Somlo, S. and Peters, D.J.M. (1997) A spectrum of mutations in the second gene for autosomal dominant polycystic kidney (PKD2). Am. J. Hum. Genet., 61, 547-555. MEDLINE Abstract

6. Qian, F., Germino, E.J., Cai, Y., Zhang, X., Somlo, S. and Germino, G.G. (1997) PKD1 interacts with PKD2 through a probable coiled-coil domain. Nature Genet., 16, 179-183. MEDLINE Abstract

7. Tsiokas, L., Kim, E., Arnould, T., Sukhatme, V.P. and Walz, G. (1997) Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc. Natl Acad. Sci. USA, 94, 6965-6970. MEDLINE Abstract

8. Qian, F., Watnick, T.J., Luiz, F., Onuchic, L.F. and Germino, G.G. (1996) The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type 1. Cell, 87, 979-987. MEDLINE Abstract

9. Brasier, J.L. and Henske, E.P. (1997) Loss of the polycystic kidney disease (PKD1) region of 16p13 in renal cyst cells supports a loss-of-function model for cyst pathogenesis. J. Clin. Invest., 99, 194-199.

10. Koptides, M., Constantinides, R., Kyriakides, G., Hadjigavriel, M., Patsalis, P.C., Pierides, A. and Constantinou Deltas, C. (1998) Loss of heterozygosity in polycystic kidney disease with a missense mutation in the repeated region of PKD1. Hum. Genet., 103, 709-717. MEDLINE Abstract

11. Watnick, T.J., Torres, V.E., Gandolph, M.A., Qian, F., Onuchic, L.F., Klinger, K.W., Landes, G. and Germino, G.G. (1998) Somatic mutation in individual liver cysts supports a two-hit model for cystogenesis in autosomal dominant polycystic kidney disease. Mol. Cell, 2, 247-251. MEDLINE Abstract

12. Wu, G., Dagati, V., Cai, Y., Markowitz, G., Park, J.H., Reynolds, D.M., Maeda, Y., Le, T.C., Hou, H. Jr, Kucherlapati, R., Edelmann, W. and Somlo, S. (1998) Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell, 93, 177-188. MEDLINE Abstract

13. Reeders, S.T. (1992) Multilocus polycystic disease. Nature Genet., 1, 235-237. MEDLINE Abstract

14. Xenophontos, S., Constantinides, R., Hayashi, T., Mochizuki, T., Somlo, S., Pierides, A. and Constantinou Deltas, C. (1997) A translation frameshift mutation induced by a cytosine insertion in the polycystic kidney disease 2 gene (PKD2). Hum. Mol. Genet., 6, 949-952. MEDLINE Abstract

15. Ong, A.C.M. and Harris, P.C. (1997) Molecular basis of renal cyst formation-one hit or two. Lancet, 349, 1039-1040. MEDLINE Abstract

16. Tischfield, J.A. (1997) Loss of heterozygosity or: how I learned to stop worrying and love mitotic recombination. Am. J. Hum. Genet., 61, 995-999. MEDLINE Abstract

17. Knudson, A.G. (1993) Antioncogenes and human cancer. Proc. Natl Acad. Sci. USA, 90, 10914-10921. MEDLINE Abstract

18. Grantham, J.J. (1990) Polycystic kidney disease: neoplasia in disguise. Am. J. Kidney Dis., 15, 110-116.

19. Constantinou Deltas, C., Papageorgiou, E., Boteva, K., Christodoulou, K., Breuning, M.H., Peters, D.J.M. and Pierides, A. (1995) Genetic heterogeneity in adult dominant polycystic kidney disease in Cypriot families. Hum. Genet., 95, 416-423. MEDLINE Abstract

20. Hayashi, T., Mochizuki, T., Reynolds, D.M., Wu, G., Cai, Y. and Somlo, S. (1997) Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2). Genomics, 44, 131-136. MEDLINE Abstract

*To whom correspondence should be addressed. Tel: +357 2 392655; Fax: +357 2 358237; Email: deltasco@mdrtc.cing.ac.cy

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