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PKD1  -  polycystic kidney disease 1 (autosomal...

Homo sapiens

Synonyms: Autosomal dominant polycystic kidney disease 1 protein, PBP, Pc-1, Polycystin-1, TRPP1
 
 
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Disease relevance of PKD1

  • Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome [1].
  • Mutations of either PKD1 or PKD2 cause autosomal dominant polycystic kidney disease, a syndrome characterized by extensive formation of renal cysts and progressive renal failure [2].
  • There is no evidence of linkage to PKDL in six ADPKD families that are unlinked to PKD1 or PKD2 [3].
  • In PKD2 cystic kidney and liver, we find polycystin-2 expression in the majority of cysts, although a significant minority are negative, a pattern mirrored by the PKD1 protein [4].
  • Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families) [5].
  • PKD gene type, gender, proteinuria, and the presence of hypertension relate to the rate of kidney growth in ADPKD [6].
 

Psychiatry related information on PKD1

 

High impact information on PKD1

  • The genetic defect in ADPKD may not directly affect membrane transport mechanisms but rather may arrest the development of certain renal epithelial cells in an incompletely differentiated, proliferative stage [11].
  • Cysts also appear in the intrahepatic biliary tree in ADPKD [11].
  • Clonal somatic mutations of PKD1 were identified in a subset of cysts that lacked PKD2 mutations [12].
  • As in human ADPKD, formation of kidney cysts in adult Pkd2WS25/- mice is associated with renal failure and early death (median survival, 65 weeks versus 94 weeks for controls) [13].
  • Our studies advance our understanding of the function of polycystin-2 in development and our mouse models recapitulate the complex human ADPKD phenotype [13].
 

Chemical compound and disease context of PKD1

 

Biological context of PKD1

  • LOV-1 is the closest C. elegans homologue of PKD1. lov-1 is expressed in adult males in sensory neurons of the rays, hook and head, which mediate response, vulva location, and potentially chemotaxis to hermaphrodites, respectively [19].
  • Inspection of the haplotypes of these individuals suggested the possibility of bilineal disease from independently segregating PKD1 and PKD2 mutations [20].
  • No LOH for the PKD1 gene or locus D3S1478 were observed in those cysts, which demonstrates that somatic alterations are specific [21].
  • Additionally, when the disease status of these individuals was coded as "unknown" in linkage analysis, we also found, with markers at the PKD1 locus, significant LOD scores (i.e., >3.0) [20].
  • A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype [22].
 

Anatomical context of PKD1

 

Associations of PKD1 with chemical compounds

  • Thereafter, PKD2 is diffusely expressed at all stages of nephron development, whereas high PKD1 expression first appears in differentiated proximal tubules [27].
  • The PKD1 gene product is likely to be a very large membrane-associated glycoprotein that functions as a receptor for cell-cell or cell-matrix interactions [28].
  • These data identify tuberin as a determinant of polycystin-1 functional localization and, potentially, ADPKD severity [29].
  • Recent evidence has shown that ADPKD cells also have an altered responsiveness to cyclic AMP [30].
  • We describe the identification of a missense mutation in the repeated part of the PKD1 gene, exon 31, that substitutes valine for methionine [31].
 

Physical interactions of PKD1

  • One domain involves a minimal region of 73 amino acids in the C-terminal cytoplasmic tail of PKD2 shown previously to constitute an interacting domain with PKD1 [32].
  • We now show that apical localization of EGFR complexes in normal fetal and ADPKD epithelia is associated with heterodimerization of EGFR(HER-1) with HER-2(neu/ErbB2), while basal membrane localization in normal adult renal epithelia is associated with EGFR(HER-1) homodimers [33].
  • Tuberous sclerosis complex and early-onset autosomal dominant polycystic kidney disease as a 'contiguous gene' syndrome: report of a case [34].
  • Changes in extracellular matrix (ECM) are regarded to be an important pathogenic factor connected with the genes assumed to be responsible for human ADPKD [35].
  • It is concluded that ouabain stimulates proliferation in ADPKD cells by binding to the Na,K-ATPase with high affinity and via activation of the MEK-ERK pathway [36].
 

Enzymatic interactions of PKD1

  • These findings support a role for PKD1 in the control of pathological remodeling of the heart via its ability to phosphorylate and neutralize HDAC5 [37].
  • In vitro kinase assays have shown that PKD1 phosphorylates E-cadherin [38].
 

Co-localisations of PKD1

 

Regulatory relationships of PKD1

 

Other interactions of PKD1

  • We have identified large deletions disrupting TSC2 and PKD1 in each of six such cases studied [1].
  • Mutations in either PKD1 or PKD2 are associated with ADPKD but the function of these genes is unknown [44].
  • However, distinct residues within this region mediate specific interactions with TRPC1 or PKD1 [32].
  • Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1 [45].
  • We report a 3-month-old Caucasian girl of non-consanguineous parents with TSC and early manifestation of ADPKD [46].
 

Analytical, diagnostic and therapeutic context of PKD1

References

  1. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome. Brook-Carter, P.T., Peral, B., Ward, C.J., Thompson, P., Hughes, J., Maheshwar, M.M., Nellist, M., Gamble, V., Harris, P.C., Sampson, J.R. Nat. Genet. (1994) [Pubmed]
  2. The polycystin-1 C-terminal fragment triggers branching morphogenesis and migration of tubular kidney epithelial cells. Nickel, C., Benzing, T., Sellin, L., Gerke, P., Karihaloo, A., Liu, Z.X., Cantley, L.G., Walz, G. J. Clin. Invest. (2002) [Pubmed]
  3. Identification of PKDL, a novel polycystic kidney disease 2-like gene whose murine homologue is deleted in mice with kidney and retinal defects. Nomura, H., Turco, A.E., Pei, Y., Kalaydjieva, L., Schiavello, T., Weremowicz, S., Ji, W., Morton, C.C., Meisler, M., Reeders, S.T., Zhou, J. J. Biol. Chem. (1998) [Pubmed]
  4. Coordinate expression of the autosomal dominant polycystic kidney disease proteins, polycystin-2 and polycystin-1, in normal and cystic tissue. Ong, A.C., Ward, C.J., Butler, R.J., Biddolph, S., Bowker, C., Torra, R., Pei, Y., Harris, P.C. Am. J. Pathol. (1999) [Pubmed]
  5. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. Magistroni, R., He, N., Wang, K., Andrew, R., Johnson, A., Gabow, P., Dicks, E., Parfrey, P., Torra, R., San-Millan, J.L., Coto, E., Van Dijk, M., Breuning, M., Peters, D., Bogdanova, N., Ligabue, G., Albertazzi, A., Hateboer, N., Demetriou, K., Pierides, A., Deltas, C., St George-Hyslop, P., Ravine, D., Pei, Y. J. Am. Soc. Nephrol. (2003) [Pubmed]
  6. Autosomal dominant polycystic kidney disease: time for a change? Chapman, A.B. J. Am. Soc. Nephrol. (2007) [Pubmed]
  7. Is there evidence for anticipation in autosomal-dominant polycystic kidney disease? Fick, G.M., Johnson, A.M., Gabow, P.A. Kidney Int. (1994) [Pubmed]
  8. Effect of enalapril on blood pressure, renal function, and the renin-angiotensin-aldosterone system in cats with autosomal dominant polycystic kidney disease. Miller, R.H., Lehmkuhl, L.B., Smeak, D.D., DiBartola, S.P., Radin, J. Am. J. Vet. Res. (1999) [Pubmed]
  9. Right not to know or duty to know? Prenatal screening for polycystic renal disease. Kielstein, R., Sass, H.M. The Journal of medicine and philosophy. (1992) [Pubmed]
  10. Attributable risk of common and rare determinants of subarachnoid hemorrhage. Ruigrok, Y.M., Buskens, E., Rinkel, G.J. Stroke (2001) [Pubmed]
  11. Epithelial transport in polycystic kidney disease. Sullivan, L.P., Wallace, D.P., Grantham, J.J. Physiol. Rev. (1998) [Pubmed]
  12. Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations. Watnick, T., He, N., Wang, K., Liang, Y., Parfrey, P., Hefferton, D., St George-Hyslop, P., Germino, G., Pei, Y. Nat. Genet. (2000) [Pubmed]
  13. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Wu, G., Markowitz, G.S., Li, L., D'Agati, V.D., Factor, S.M., Geng, L., Tibara, S., Tuchman, J., Cai, Y., Park, J.H., van Adelsberg, J., Hou, H., Kucherlapati, R., Edelmann, W., Somlo, S. Nat. Genet. (2000) [Pubmed]
  14. Comparative analysis of the polycystic kidney disease 1 (PKD1) gene reveals an integral membrane glycoprotein with multiple evolutionary conserved domains. Sandford, R., Sgotto, B., Aparicio, S., Brenner, S., Vaudin, M., Wilson, R.K., Chissoe, S., Pepin, K., Bateman, A., Chothia, C., Hughes, J., Harris, P. Hum. Mol. Genet. (1997) [Pubmed]
  15. Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression. Prawitt, D., Enklaar, T., Klemm, G., Gärtner, B., Spangenberg, C., Winterpacht, A., Higgins, M., Pelletier, J., Zabel, B. Hum. Mol. Genet. (2000) [Pubmed]
  16. Modifier genes play a significant role in the phenotypic expression of PKD1. Fain, P.R., McFann, K.K., Taylor, M.R., Tison, M., Johnson, A.M., Reed, B., Schrier, R.W. Kidney Int. (2005) [Pubmed]
  17. Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease. Baboolal, K., Ravine, D., Daniels, J., Williams, N., Holmans, P., Coles, G.A., Williams, J.D. Kidney Int. (1997) [Pubmed]
  18. Proliferative activity of cyst epithelium in human renal cystic diseases. Nadasdy, T., Laszik, Z., Lajoie, G., Blick, K.E., Wheeler, D.E., Silva, F.G. J. Am. Soc. Nephrol. (1995) [Pubmed]
  19. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Barr, M.M., Sternberg, P.W. Nature (1999) [Pubmed]
  20. Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease. Pei, Y., Paterson, A.D., Wang, K.R., He, N., Hefferton, D., Watnick, T., Germino, G.G., Parfrey, P., Somlo, S., St George-Hyslop, P. Am. J. Hum. Genet. (2001) [Pubmed]
  21. A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2. Torra, R., Badenas, C., San Millán, J.L., Pérez-Oller, L., Estivill, X., Darnell, A. Am. J. Hum. Genet. (1999) [Pubmed]
  22. A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Pritchard, L., Sloane-Stanley, J.A., Sharpe, J.A., Aspinwall, R., Lu, W., Buckle, V., Strmecki, L., Walker, D., Ward, C.J., Alpers, C.E., Zhou, J., Wood, W.G., Harris, P.C. Hum. Mol. Genet. (2000) [Pubmed]
  23. The mouse homologue of the polycystic kidney disease gene (Pkd1) is a single-copy gene. Olsson, P.G., Löhning, C., Horsley, S., Kearney, L., Harris, P.C., Frischauf, A. Genomics (1996) [Pubmed]
  24. Polycystins: polymodal receptor/ion-channel cellular sensors. Delmas, P. Pflugers Arch. (2005) [Pubmed]
  25. Molecular basis of autosomal dominant polycystic kidney disease. Al-Bhalal, L., Akhtar, M. Advances in anatomic pathology. (2005) [Pubmed]
  26. Type identification of autosomal dominant polycystic kidney disease by analysis of fluorescent short tandem repeat markers. Lin, W.D., Wu, J.Y., Tsai, F.J., Gau, M.T., Lee, C.C. J. Formos. Med. Assoc. (2002) [Pubmed]
  27. Expression of PKD1 and PKD2 transcripts and proteins in human embryo and during normal kidney development. Chauvet, V., Qian, F., Boute, N., Cai, Y., Phakdeekitacharoen, B., Onuchic, L.F., Attié-Bitach, T., Guicharnaud, L., Devuyst, O., Germino, G.G., Gubler, M.C. Am. J. Pathol. (2002) [Pubmed]
  28. Molecular basis of autosomal dominant polycystic kidney disease. Watnick, T., Germino, G.G. Semin. Nephrol. (1999) [Pubmed]
  29. Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Kleymenova, E., Ibraghimov-Beskrovnaya, O., Kugoh, H., Everitt, J., Xu, H., Kiguchi, K., Landes, G., Harris, P., Walker, C. Mol. Cell (2001) [Pubmed]
  30. The genetics and physiology of polycystic kidney disease. Calvet, J.P., Grantham, J.J. Semin. Nephrol. (2001) [Pubmed]
  31. Loss of heterozygosity in polycystic kidney disease with a missense mutation in the repeated region of PKD1. Koptides, M., Constantinides, R., Kyriakides, G., Hadjigavriel, M., Patsalis, P.C., Pierides, A., Deltas, C.C. Hum. Genet. (1998) [Pubmed]
  32. Specific association of the gene product of PKD2 with the TRPC1 channel. Tsiokas, L., Arnould, T., Zhu, C., Kim, E., Walz, G., Sukhatme, V.P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  33. Inhibition of HER-2(neu/ErbB2) restores normal function and structure to polycystic kidney disease (PKD) epithelia. Wilson, S.J., Amsler, K., Hyink, D.P., Li, X., Lu, W., Zhou, J., Burrow, C.R., Wilson, P.D. Biochim. Biophys. Acta (2006) [Pubmed]
  34. Tuberous sclerosis complex and early-onset autosomal dominant polycystic kidney disease as a 'contiguous gene' syndrome: report of a case. Mancino, C., Balducci, A. Contributions to nephrology. (1997) [Pubmed]
  35. Coexpression of extracellular matrix glycoproteins undulin and tenascin in human autosomal dominant polycystic kidney disease. Klingel, R., Ramadori, G., Schuppan, D., Knittel, T., Meyer zum Büschenfelde, K.H., Köhler, H. Nephron (1993) [Pubmed]
  36. Ouabain Binds with High Affinity to the Na,K-ATPase in Human Polycystic Kidney Cells and Induces Extracellular Signal-Regulated Kinase Activation and Cell Proliferation. Nguyen, A.N., Wallace, D.P., Blanco, G. J. Am. Soc. Nephrol. (2007) [Pubmed]
  37. Regulation of cardiac stress signaling by protein kinase d1. Harrison, B.C., Kim, M.S., van Rooij, E., Plato, C.F., Papst, P.J., Vega, R.B., McAnally, J.A., Richardson, J.A., Bassel-Duby, R., Olson, E.N., McKinsey, T.A. Mol. Cell. Biol. (2006) [Pubmed]
  38. E-cadherin phosphorylation by protein kinase D1/protein kinase C{mu} is associated with altered cellular aggregation and motility in prostate cancer. Jaggi, M., Rao, P.S., Smith, D.J., Wheelock, M.J., Johnson, K.R., Hemstreet, G.P., Balaji, K.C. Cancer Res. (2005) [Pubmed]
  39. Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Tsiokas, L., Kim, E., Arnould, T., Sukhatme, V.P., Walz, G. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  40. Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition. Kim, H., Bae, Y., Jeong, W., Ahn, C., Kang, S. Eur. J. Hum. Genet. (2004) [Pubmed]
  41. Basolateral chloride transporters in autosomal dominant polycystic kidney disease. Lebeau, C., Hanaoka, K., Moore-Hoon, M.L., Guggino, W.B., Beauwens, R., Devuyst, O. Pflugers Arch. (2002) [Pubmed]
  42. Impaired formation of desmosomal junctions in ADPKD epithelia. Russo, R.J., Husson, H., Joly, D., Bukanov, N.O., Patey, N., Knebelmann, B., Ibraghimov-Beskrovnaya, O. Histochem. Cell Biol. (2005) [Pubmed]
  43. Ets factors regulate the polycystic kidney disease-1 promoter. Puri, S., Rodova, M., Islam, M.R., Magenheimer, B.S., Maser, R.L., Calvet, J.P. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  44. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Hanaoka, K., Qian, F., Boletta, A., Bhunia, A.K., Piontek, K., Tsiokas, L., Sukhatme, V.P., Guggino, W.B., Germino, G.G. Nature (2000) [Pubmed]
  45. Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1. Harris, P.C. Curr. Opin. Nephrol. Hypertens. (2002) [Pubmed]
  46. Tuberous sclerosis and polycystic kidney disease in a 3-month-old infant. Laass, M.W., Spiegel, M., Jauch, A., Hahn, G., Rupprecht, E., Vogelberg, C., Bartsch, O., Huebner, A. Pediatr. Nephrol. (2004) [Pubmed]
  47. Immortalized epithelial cells from human autosomal dominant polycystic kidney cysts. Loghman-Adham, M., Nauli, S.M., Soto, C.E., Kariuki, B., Zhou, J. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  48. The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease. Sandford, R., Mulroy, S., Foggensteiner, L. Cell. Mol. Life Sci. (1999) [Pubmed]
  49. Mutation analysis in PKD1 of Japanese autosomal dominant polycystic kidney disease patients. Inoue, S., Inoue, K., Utsunomiya, M., Nozaki, J., Yamada, Y., Iwasa, T., Mori, E., Yoshinaga, T., Koizumi, A. Hum. Mutat. (2002) [Pubmed]
 
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