*173910 POLYCYSTIC KIDNEY DISEASE 2; PKD2

Alternative titles; symbols

POLYCYSTIN-2
POLYCYSTIC KIDNEY DISEASE, TYPE 2
POLYCYSTIC KIDNEY DISEASE, ADULT, TYPE II, INCLUDED; APKD2, INCLUDED
POLYCYSTIC KIDNEY DISEASE 4, INCLUDED; PKD4, INCLUDED

TABLE OF CONTENTS

TEXT

ALLELIC VARIANTS

• View List of allelic variants

REFERENCES

CONTRIBUTORS

CREATION DATE

EDIT HISTORY

CLINICAL SYNOPSIS

Database Links

Gene Map Locus: 4q21-q23

TEXT

Bear et al. (1992) Ravine et al. (1992) reported families in which the polycystic kidney disease did not cosegregate with chromosome 16 markers, the age of onset of end stage renal disease (ESRD) was later (68.7 years) than in persons with chromosome 16 related disease (56.3 years). Ravine et al. (1992) analyzed 18 families (285 affected members) with mutations at the PKD1 locus and 5 families (49 affected persons) in which involvement at this locus was dismissed. Non-PKD1 patients lived longer than PKD1 patients (median survival, 71.5 vs 56.0 years, respectively), had a lower risk of progressing to renal failure, were less likely to have hypertension, were diagnosed at an older age, and had fewer renal cysts at the time of diagnosis.

In 8 Spanish families with APKD unlinked to 16p13.3, San Millan et al. (1995)by multipoint linkage analysis, as well as a study of recombinant haplotypes, placed the PKD2 locus between D4S1542 and D4S1563, which defines a genetic interval of approximately 1 cM. They confirmed earlier findings of a milder phenotype with PKD2. While the mean age of onset of end-stage renal disease (EDRD) was 54.2 +/- 8.1 years for PKD1, it was 66.2 +/- 3.3 years for PKD2.

Mochizuki et al. (1996) reported the isolation and characterization of a candidate gene for PKD2 on chromosome 4. The gene, which contains a 2,904-bp open reading frame and a 2,086-bp untranslated region, extends over 68 kb. It is strongly expressed in ovary, fetal and adult kidney, testis, and small intestine. Mochizuki et al. (1996) detected no expression of the gene in peripheral leukocytes. The predicted translation product is a 968-amino acid polypeptide which appears to be an integral membrane protein with 6 membrane-spanning domains and intracellular N and C termini. There is 25% identity and 50% similarity between the putative translation product of PKD2 and the 450-amino acid product of the PKD1 gene. There is a similar degree of homology between the putative PKD2 locus product and that of the voltage-activated calcium channel-alpha-1E gene (see 601012). Hayashi et al. (1997) found that the PKD2 gene has at least 15 exons with the translation start site in exon 1.

Mochizuki et al. (1996) analyzed the PKD2 gene in affected individuals in 3 families with type 2 polycystic kidney disease. They used reverse-transcribed RNA and genomic DNA templates to generate PCR products for SSCP analysis and sequencing. Three nonsense mutations in the PKD2 gene were identified in affected individuals; see 173910.0001, 173910.0002, and 173910.0003. These mutations were not present in controls. Schneider et al. (1996) likewise cloned the PKD2 gene.

It was suggested that the different forms of autosomal dominant polycystic kidney disease, PKD1 and PKD2, and perhaps a third form result from defects in interactive factors involved in a common pathway. The discovery of the genes for the 2 most common forms of ADPKD provided an opportunity to test this hypothesis. Qian et al. (1997) described a previously unrecognized coiled-coil domain within the C terminus of the PKD1 gene product, polycystin-1, and demonstrated that it binds specifically to the C terminus of PKD2. Homotypic interactions involving the C terminus of each were also demonstrated. They showed that naturally occurring pathogenic mutations of PKD1 and PKD2 disrupt their associations. Qian et al. (1997) suggested that PKD1 and PKD2 associate physically in vivo and may be partners of a common signaling cascade involved in tubular morphogenesis.

Tsiokas et al. (1997) showed that PKD1 and PKD2 interact through their C-terminal cytoplasmic tails. This interaction results in up-regulation of PKD1 but not PKD2. Furthermore, the cytoplasmic tail of PKD2 but not PKD1 forms homodimers through a coiled-coil domain distinct from the region required for interaction with PKD1. These interactions suggested that PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis and that PKD1 requires the presence of PKD2 for stable expression.

ALLELIC VARIANTS

.0001 POLYCYSTIC KIDNEY DISEASE, TYPE 2 [PKD2, TRP380TER ]

In affected members of a family with chromosome 4-linked polycystic kidney disease type 2, Mochizuki et al. (1996) identified a G-to-A transition in the PKD2 gene that resulted in a change at codon 380 from trp to stop.

.0002 POLYCYSTIC KIDNEY DISEASE, TYPE 2 [PKD2, ARG742TER ]

In affected members of a Cypriot family with chromosome 4-linked polycystic kidney disease type 2, Mochizuki et al. (1996) identified a C-to-T transition in the PKD2 gene that resulted in a change at codon 740 from arg to stop.

.0003 POLYCYSTIC KIDNEY DISEASE, TYPE 2 [PKD2, GLN405TER ]

In a second unrelated Cypriot family with chromosome 4-linked polycystic kidney disease type 2, Mochizuki et al. (1996) identified a C-to-T transition in the PKD2 gene that resulted in a change at codon 405 from gln to stop.

.0004 POLYCYSTIC KIDNEY DISEASE, TYPE 2 [PKD2, 1-BP INS, FS269TER ]

In Cyprus, there are at least 3 kindreds with PKD2, documented by linkage analysis. The mutations were arg742ter (173910.0002) and gln405ter (173910.0003), respectively. Xenophontos et al. (1997) defined the mutation in the third family by systematically screening the entire coding sequence of the PKD2 gene by SSCP analysis and heteroduplex formation. A novel mutation was identified in exon 2, where a new cytosine residue was inserted immediately after codon 231. It caused a translation frameshift and was expected to lead to the introduction of 37 novel amino acids before the translation reached a new stop codon. This was the most N-terminal mutation reported to that time, and based on the protein's modeled structure, it was predicted to be within the first transmembrane domain.

REFERENCES

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Linkage study of a large family with autosomal dominant polycystic kidney disease with reduced expression: absence of linkage to the PKD1 locus. Hum. Genet. 85: 221-227, 1990.
PubMed ID : 2370053

2. Bear, J. C.; Parfrey, P. S.; Morgan, J. M.; Martin, C. J.; Cramer, B. C. :

Autosomal dominant polycystic kidney disease: new information for genetic counselling. Am. J. Med. Genet. 43: 548-553, 1992.
PubMed ID : 1605247

3. Coto, E.; Aguado, S.; Alvarez, J.; Menendez Diaz, M. J.; Lopez-Larrea, C. :

Genetic and clinical studies in autosomal dominant polycystic kidney disease type 1 (ADPKD1). J. Med. Genet. 29: 243-246, 1992.
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4. Coto, E.; Sanz de Castro, S.; Aguado, S.; Alvarez, J.; Arias, M.; Menendez, M. J.; Lopez-Larrea, C. :

DNA microsatellite analysis of families with autosomal dominant polycystic kidney disease types 1 and 2: evaluation of clinical heterogeneity between both forms of the disease. J. Med. Genet. 32: 442-445, 1995.
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5. Elles, R. G.; Read, A. P.; Hodgkinson, K. A.; Watters, A.; Harris, R. :

Recombination or heterogeneity: is there a second locus for adult polycystic kidney disease? J. Med. Genet. 27: 413-417, 1990.
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6. Fossdal, R.; Boovarsson, M.; Asmundsson, P.; Ragnarsson, J.; Peters, D.; Breuning, M. H.; Jensson, O. :

Icelandic families with autosomal dominant polycystic kidney disease: families unlinked to chromosome 16p13.3 revealed by linkage analysis. Hum. Genet. 91: 609-613, 1993.
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7. Hayashi, T.; Mochizuki, T.; Reynolds, D. M.; Wu, G.; Cai, Y.; Somlo, S. :

Characterization of the exon structure of the polycystic kidney disease 2 gene (PKD2). Genomics 44: 131-136, 1997.
PubMed ID : 9286709

8. Jeffery, S.; Saggar-Malik, A. K.; Morgan, S.; MacGregor, G. A. :

A family with autosomal dominant polycystic kidney disease not linked to chromosome 16p13.3. Clin. Genet. 44: 173-176, 1993.
PubMed ID : 8261645

9. Kimberling, W. J.; Fain, P. R.; Kenyon, J. B.; Goldgar, D.; Sujansky, E.; Gabow, P. A. :

Linkage heterogeneity of autosomal dominant polycystic kidney disease. New Eng. J. Med. 319: 913-918, 1988.
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10. Kimberling, W. J.; Kumar, S.; Gabow, P. A.; Kenyon, J. B.; Connolly, C. J.; Somlo, S. :

Autosomal dominant polycystic kidney disease: localization of the second gene to chromosome 4q13-q23. Genomics 18: 467-472, 1993.
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11. Kumar, S.; Kimberling, W. J.; Gabow, P. A.; Kenyon, J. B. :

Genetic linkage studies of autosomal dominant polycystic kidney disease: search for the second gene in a large Sicilian family. Hum. Genet. 87: 129-133, 1991.
PubMed ID : 1676697

12. Kumar, S.; Kimberling, W. J.; Gabow, P. A.; Shugart, Y. Y.; Pieke-Dahl, S. :

Exclusion of autosomal dominant polycystic kidney disease type II (ADPKD2) from 160 cM of chromosome 1. J. Med. Genet. 27: 697-700, 1990.
PubMed ID : 1980516

13. Mochizuki, T.; Wu, G.; Hayashi, T.; Xenophontos, S. L.; Veldhuisen, B.; Saris, J. J.; Reynolds, D. M.; Cai, Y.; Gabow, P. A.; Pierides, A.; Kimberling, W. J.; Breuning, M. H.; Constantinou Deltas, C.; Peters, D. J. M.; Somlo, S. :

PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272: 1339-1342, 1996.
PubMed ID : 8650545

14. Norby, S.; Schwartz, M. :

Possible locus for polycystic kidney disease on chromosome 2.(Letter) Lancet 336: 323-324, 1990.
PubMed ID : 1974020

15. Peters, D. J. M.; Spruit, L.; Saris, J. J.; Ravine, D.; Sandkuijl, L. A.; Fossdal, R.; Boersma, J.; van Eijk, R.; Norby, S.; Constantinou-Deltas, C. D.; Pierides, A.; Brissenden, J. E.; Frants, R. R.; van Ommen, G.-J. B.; Breuning, M. H. :

Chromosome 4 localization of a second gene for autosomal dominant polycystic kidney disease. Nature Genet. 5: 359-362, 1993.
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16. Pieke, S. A.; Kimberling, W. J.; Kenyon, J. B.; Gabow, P. :

Genetic heterogeneity of polycystic kidney disease: an estimate of the proportion of families unlinked to chromosome 16.(Abstract) Am. J. Hum. Genet. 45 (suppl.): A58 only, 1989.

17. Qian, F.; Germino, F. J.; Cai, Y.; Zhang, X.; Somlo, S.; Germino, G. G. :

PKD1 interacts with PKD2 through a probable coiled-coil domain. Nature Genet. 16: 179-183, 1997.
PubMed ID : 9171830

18. Ravine, D.; Walker, R. G.; Gibson, R. N.; Forrest, S. M.; Richards, R. I.; Friend, K.; Sheffield, L. J.; Kincaid-Smith, P.; Danks, D. M. :

Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease. Lancet 340: 1330-1333, 1992.
PubMed ID : 1360045

19. Romeo, G.; Devoto, M.; Costa, G.; Roncuzzi, L.; Catizone, L.; Zucchelli, P.; Germino, G.-G.; Keith, T.; Weatherall, D. J.; Reeders, S. T. :

A second genetic locus for autosomal dominant polycystic kidney disease. Lancet II: 8-11, 1988.
PubMed ID : 2898665

20. San Millan, J. L.; Viribay, M.; Peral, B.; Martinez, I.; Weissenbach, J.; Moreno, F. :

Refining the localization of the PKD2 locus on chromosome 4q by linkage analysis in Spanish families with autosomal dominant polycystic kidney disease type 2. Am. J. Hum. Genet. 56: 248-253, 1995.
PubMed ID : 7825585

21. Schneider, M. C.; Rodriguez, A. M.; Nomura, H.; Zhou, J.; Morton, C. C.; Reeders, S. T.; Weremowicz, S. :

A gene similar to PKD1 maps to chromosome 4q22: a candidate gene for PKD2. Genomics 38: 1-4, 1996.
PubMed ID : 8954772

22. Tsiokas, L.; Kim, E.; Arnould, T.; Sukhatme, V. P.; Walz, G. :

Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc. Nat. Acad. Sci. 94: 6965-6970, 1997.
PubMed ID : 9192675

23. Wu, G.; Mochizuki, T.; Le, T. C.; Cai, Y.; Hayashi, T.; Reynolds, D. M.; Somlo, S. :

Molecular cloning, cDNA sequence analysis, and chromosomal localization of mouse Pkd2. Genomics 45: 220-223, 1997.

24. Xenophontos, S.; Constantinides, R.; Hayashi, T.; Mochizuki, T.; Somlo, S.; Pierides, A.; Constantinou Deltas, C. :

A transition frameshift mutation induced by a cytosine insertion in the polycystic kidney disease 2 gene (PKD2). Hum. Molec. Genet. 6: 949-952, 1997.
PubMed ID : 9175744

25. Zerres, K.; Mucher, G.; Rudnik-Schoneborn, S. :

Autosomal recessive polycystic kidney disease does not map to the second gene locus for autosomal dominant polycystic kidney disease on chromosome 4. Hum. Genet. 93: 697-698, 1994.
PubMed ID : 8005596

26. Zerres, K.; Volpel, M. C.; Weiss, H. :

Cystic kidneys: genetics, pathologic anatomy, clinical picture, and prenatal diagnosis. Hum. Genet. 68: 104-135, 1984.
PubMed ID : 6500563

CLINICAL SYNOPSIS