Nephronophthisis: disease mechanisms of a ciliopathy

J Am Soc Nephrol. 2009 Jan;20(1):23-35. doi: 10.1681/ASN.2008050456. Epub 2008 Dec 31.


Nephronophthisis (NPHP), a recessive cystic kidney disease, is the most frequent genetic cause of end-stage kidney disease in children and young adults. Positional cloning of nine genes (NPHP1 through 9) and functional characterization of their encoded proteins (nephrocystins) have contributed to a unifying theory that defines cystic kidney diseases as "ciliopathies." The theory is based on the finding that all proteins mutated in cystic kidney diseases of humans or animal models are expressed in primary cilia or centrosomes of renal epithelial cells. Primary cilia are sensory organelles that connect mechanosensory, visual, and other stimuli to mechanisms of epithelial cell polarity and cell-cycle control. Mutations in NPHP genes cause defects in signaling mechanisms that involve the noncanonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance. The ciliary theory explains the multiple organ involvement in NPHP, which includes retinal degeneration, cerebellar hypoplasia, liver fibrosis, situs inversus, and mental retardation. Positional cloning of dozens of unknown genes that cause NPHP will elucidate further signaling mechanisms involved. Nephrocystins are highly conserved in evolution, thereby allowing the use of animal models to develop future therapeutic approaches.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Calmodulin-Binding Proteins / genetics
  • Cell Polarity
  • Cilia / pathology*
  • Cytoskeletal Proteins
  • Humans
  • Kidney Diseases, Cystic / etiology*
  • Kidney Diseases, Cystic / pathology
  • Kinesins / genetics
  • Kruppel-Like Transcription Factors / physiology
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / genetics
  • Membrane Proteins / genetics
  • Proteins / genetics
  • Retinal Degeneration / etiology
  • Retinal Degeneration / genetics
  • Situs Inversus / etiology
  • Situs Inversus / genetics
  • Transcription Factors / physiology


  • Adaptor Proteins, Signal Transducing
  • Calmodulin-Binding Proteins
  • Cytoskeletal Proteins
  • GLIS2 protein, human
  • INVS protein, human
  • IQCB1 protein, human
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • NPHP1 protein, human
  • NPHP4 protein, human
  • Proteins
  • Transcription Factors
  • nephrocystin-3, human
  • Kinesins