Abstract
Characterization of the polycystic kidney disease 1 (PKD1) gene has been complicated by genomic rearrangements on chromosome 16. We have used an exon linking strategy, taking RNA from a cell line containing PKD1 but not the duplicate loci, to clone a cDNA contig of the entire transcript. The transcript consists of 14,148 bp (including a correction to the previously described C terminus), distributed among 46 exons spanning 52 kb. The predicted PKD1 protein, polycystin, is a glycoprotein with multiple transmembrane domains and a cytoplasmic C-tail. The N–terminal extracellular region of over 2,500 aa contains leucine–rich repeats, a C–type lectin, 16 immunoglobulin–like repeats and four type III fibronectin–related domains. Our results indicate that polycystin is an integral membrane protein involved in cell–cell/matrix interactions.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dalgaard, O.Z. Bilateral polycystic disease of the kidneys: A follow-up of two hundred and eighty-four patients and their families. Acta Med. Scand. 328, 1–251 (1957).
Gabow, P.A. Autosomal dominant polycystic kidney disease. New Engl. J. Med. 329, 332–342 (1993).
Milutinovic, J. et al. Liver cysts in patients with autosomal dominant polycystic kidney disease. Am. J. Med. 68, 741–744 (1980).
Gabow, P.A. Autosomal dominant polycystic kidney disease–more than a renal disease. Am. J. Kid. Dis. 16, 403–413 (1990).
Somlo, S. et al. A kindred exhibiting cosegregation of an overlap connective tissue disorder and the chromosome 16 linked form of autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 4, 1371–1378 (1993).
Carone, F.A., Bacallao, R. & Kanwar, Y.S. Biology of polycystic kidney disease. Lab. Invest. 70, 437–448 (1994).
Calvet, J.P. Polycystic kidney disease: primary extracellular matrix abnormality or defective cellular differentiation? Kid. Int. 43, 101–108 (1993).
Milutinovic, J., Lawrence, C.Y., Agodoa, M.D., Cutler, R.E. & Striker, G.E. Autosomal dominant polycystic kidney disease: Early diagnosis and consideration of pathogenesis. Am. J. Clin. Path. 73, 740–747 (1979).
Carone, F.A. et al. Impaired tubulogenesis of cyst-derived cells from autosomal dominant polycystic kidneys. Kid. Int. 47, 861–868 (1995).
Wilson, P.D. & Sherwood, A.C. Tubulocystic epithelium. Kid. Int. 39, 450–463 (1991).
Peters, D.J.M. et al. Chromosome 4 localization of a second gene for autosomal dominant polycystic kidney disease. Nature Genet. 5, 359–362 (1993).
Kimberling, W.J. et al. Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13–q23. Genomics. 18, 467–472 (1993).
Daoust, M.C., Reynolds, D.M., Bichet, D.G. & Somlo, S. Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics 25, 733–736 (1995).
Peters, D.J.M. & Sandkuijl, L.A. Genetic heterogeneity of polycystic kidney disease in Europe. in Contributions to Nephrology, Polycystic Kidney Disease (eds Breuning, M. H., Devoto, M. & Romeo, G.) 128–139 (Karger, Basel, 1992).
Ravine, D. et al. Phenotype and genotype heterogeneity in autosomal dominant polycystic kidney disease. Lancet 340, 1330–1333 (1992).
European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77, 881–894 (1994).
Peral, B. et al. Splicing mutations of the polycystic kidney disease 1 (PKD1) gene induced by intronic deletion. Hum. molec. Genet. 4, 569–574 (1995).
Brook-Carter, P.T. et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease-acontiguous gene syndrome. Nature Genet. 8, 328–332 (1994).
European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75, 1305–1315 (1993).
Kozak, M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs. Nucl. Adds Res. 15, 8125–8148 (1987).
von Heijne, G. A new method for predicting signal sequence cleavage sites. Nucl. Adds Res. 14, 4683–4691 (1986).
Kobe, B. & Deisenhofer, J. The leucine-rich repeat: a versatile binding motif. Trends Biochem. Sci. 19, 415–421 (1994).
Rothberg, J.M., Jacobs, J.R., Goodman, C.S. & Artavanis-Tsakonas, S. slit: an extracellular protein necessary for development of midline glia and commissural axon pathways contains both EGF and LRR domains. Genes Dev. 4, 2169–2187 (1990).
Oldberg, Å., Antonsson, P., Lindblom, K. & Heinegard, D. A collagen-binding 59-kd protein (fibromodulin) is structurally related to the small interstitial proteoglycans PG-S1 and PG-S2 (decorin). EMBO J. 8, 2601–2604 (1989).
Lamballe, F., Klein, R. & Barbacid, M. trkc, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell 66, 967–979 (1991).
Drickamer, K. Membrane receptors that mediate glycoprotein endocytosis: structure and biosynthesis. Kid. Int. 32, 167–180 (1987).
Drickamer, K. Two distinct classes of carbohydrate-recognition domains in animal lectins. J. biol. Chem. 263, 9557–9560 (1988).
Weis, W.I., Drickamer, K. & Hendrickson, W.A. Structure of a C-type mannose-binding protein complexed with an oligosaccharide. Nature 360, 127–134 (1992).
Oldberg, A., Antonsson, P. & Heinegard, D. The partial amino acid sequence of bovine cartilage proteoglycan, deduced from a cDNA clone, contains numerous Ser-Gly sequences arranged in homologous repeats. Biochem. J. 243, 255–259 (1987).
Taylor, M.E., Conary, J.T., Lennartz, M.R., Stahl, P.O. & Drickamer, K. Primary structure of the mannose receptor contains multiple motif resembling carbohydrate-recognition domains. J. biol. Chem. 265, 12156–12162 (1990).
Bevilacqua, M.P., Stengelin, S., Gimbrone, M.A. Jr. & Seed, B. Endothelial leukocyte adhesion molecule 1: An inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 243, 1160–1165 (1989).
Kwon, B.S. et al. A melanocyte-specific gene, Pmel 17, maps near the silver coat color locus on mouse chromosome 10 and is in a syntenic region on human chromosome 12. Proc. Natl. Acad. Sci. U.S.A. 88, 9228–9232 (1991).
Matsushita, O., Yoshihara, K., Katayama, S., Minami, J. & Okabe, A. Purification and characterisation of a Clostridium perfringens 120-Kilodalton collagenase and nucleotide sequence of the corresponding gene. J. Bacteriol. 176, 149–156 (1994).
Harpaz, Y. & Chothia, C. Many of the immunoglobulin superfamily domains in cell adhesion molecules and surface receptors belong to a new structural set which is close to that containing variable domains. J. molec. Biol. 238, 528–539 (1994).
Williams, A.F. & Barclay, A.M. The immunoglobulin superfamily - domains for cell surface recognition. A. Rev. Immunol. 6, 381–405 (1988).
Jones, E.Y., Harlos, K., Bottomley, M.J., Robinson, R.C., Driscoll, P.C. et al. Crystal structure of an integrin-binding fragment of vascular cell adhesion molecule-1 at 1.8 Å resolution. Nature 373, 539–544 (1995).
Brümmendorf, T. & Rathjen, F.G. Cell adhesion molecules 1: immunoglobulin superfamily. Protein Prof. 1, 951–1058 (1994).
Komblihtt, A.R., Umezawa, K., Vibe-Pederson, K. & Baralle, F.E. Primary structure of human fibronectin: differential splicing may generate at least 10 polypeptides from a single gene. EMBO J. 4, 1755–1759 (1985).
Streuli, M., Krueger, N.X., Hall, L.R., Schlossman, S.F. & Saito, H. A new member of the immunoglobulin superfamily that has a cytoplasmic region homologous to the leukocyte common antigen. J. exp. Med. 168, 1523–1530 (1988).
Volkmer, H., Hassel, B., Wolff, J.M., Frank, R. & Rathjen, F.G. Structure of the axonal surface recognition molecule neurofascin and its relationship to a neural subgroup of the immunoglobulin superfamily. J. Cell Biol. 118, 149–161 (1992).
Bum, T.C. et al. Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat. Hum. molec. Genet. 4, 575–582 (1995).
van Adelsberg, J.S. & Frank, D. The PKD1 gene produces a developmentally regulated protein in mesenchyme and vasculature. Nature Med. 1, 359–364 (1995).
International Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell 81, 289–298 (1995).
Roth, G.J. Developing relationships: arterial platelet adhesion, glycoprotein Ib, and leucine-rich glycoproteins. Blood 77, 5–19 (1991).
McFarland, K. C. et al. Luptropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 245, 494–499 (1989).
Chao, M.V. Neurotrophin receptors: a window into neuronal differentiation. Neuron 9, 583–593 (1992).
Jia, R. & Hanafusa, H. The proto-oncogene of v-eyk (v-ryk) is a novel receptor-type protein tyrosine kinase with extracellular Ig/FN-lll domains. J. biol. Chem. 269, 1839–1844 (1994).
Jordan, J.R. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DMA. Science 245, 1066–1072 (1989).
Gower, H.J. et al. Alternative splicing generates a secreted form of N-CAM in muscle and brain. Cell 55, 955–964 (1988).
Schäfer, K. et al. Characterisation of the Han-SPRD rat model for hereditary polycystic kidney disease. Kid. Int. 46, 134–152 (1994).
Ekblom, P. Developmentally regulated conversion of mesechyme to epithelium. FASEB J. 3, 2141–2150 (1989).
Reeders, S.T. et al. Prenatal diagnosis of autosomal dominant polycystic kidney disease with a DNA probe. Lancet 1, 6–8 (1986).
Himmelbauer, H. et al. Saturating the region of the polycystic kidney disease gene with Not I linking clones. Am. J. hum. Genet. 48, 325–334 (1991).
Henikoff, S. Unidirectional digestion with exonuclease III creates targeted breakpoints for DNA sequencing. Gene. 28, 351–359 (1984).
Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. molec. Biol. 215, 403–410 (1990).
Pearson, W.R. & Lipman, D.J. Improved tools for biological sequence comparison. Proc. Natl. Acad. Sci. U.S.A. 85, 2444–2448 (1988).
Sipos, L. & von Heijne, G. Predicting the toplogy of eukaryotic membrane proteins. Eur. J. Biochem. 213, 1333–1340 (1993).
Engelman, D.M., Steitz, T.B. & Goldman, B. Identifying nonpolar transbilayer helices into amino acid sequences of membrane proteins. A. Rev. Biophys. Chem. 15, 321–353 (1986).
Hartmann, E., Rapoport, T.A. & Lodish, H.F. Predicting the orientation of eukaryotic membrane proteins. Proc. Natl. Acad. Sd. U.S.A. 86, 5786–5790 (1989).
Nakashima, H. & Nishikawa, K. The amino acid composition is different between the cytoplasmic and extracellular sides in membrane proteins. FEBS Lett. 303, 141–146 (1992).
Takagi, T. & Cox, J.A. Primary structure of the target of calcium vector protein of amphioxus. J. biol. Chem. 265, 19721–19727 (1990).
Bork, P. & Doolittle, R.F. Fibronectin type III modules in the receptor phosphatase CD45 and tapeworm antigens. Protein Sci. 2, 1185–1187 (1993).
Kuma, K.-i., Iwabe, N. & Miyata, T. Motifs of cadherin- and fibronectin type Ill-related sequences and evolution of the receptor-type-protein tyrosine kinases: Sequence similarity between proto-oncogene ret and cadherin family. Molec. biol. Evol. 10, 539–551 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hughes, J., Ward, C., Peral, B. et al. The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 10, 151–160 (1995). https://doi.org/10.1038/ng0695-151
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0695-151
This article is cited by
-
Elevated checkpoint inhibitor expression and Treg cell number in autosomal dominant polycystic kidney disease and their correlation with disease parameters and hypertension
Clinical and Experimental Medicine (2023)
-
Drosophila melanogaster: a simple genetic model of kidney structure, function and disease
Nature Reviews Nephrology (2022)
-
PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan
npj Genomic Medicine (2022)
-
Genome-wide siRNA screening reveals several host receptors for the binding of human gut commensal Bifidobacterium bifidum
npj Biofilms and Microbiomes (2022)
-
Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT
Scientific Reports (2022)