Autosomal dominant polycystic kidney disease: Clues to pathogenesis

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutation of one of two genes: PKD1 (16p13.3) or PKD2 (4q13-23). PKD1 accounts for ~ 85% of pedigrees and is associated with significantly more severe cystic disease. The ADPKD genes encode proteins, polycystin-1 and polycystin-2, which are very different in size and structure, but which have a region of homology and may interact as part of the same complex. Polycystin-1 is a large, integral membrane protein (~ 460 kDa) predicted to be involved in cell-cell and/or cell-matrix interactions. Polycystin-2 (~ 110 kDa) is related to polycystin-1 and voltage-activated and transient receptor potential channel subunits, suggesting that the polycystins may also be associated with ion transport. A polycystin complex could regulate cellular events (that are abnormal in ADPKD) in response to specific extracellular cues, mediated by controlling cellular Ca 2+ levels and/or other signalling pathways. Recently, two further polycystin-like molecules have been identified, indicating roles for this novel protein family beyond the kidney. A wide range of different mutations to the PKD1 or PKD2 gene have been detected, most predicted to truncate and inactivate the proteins. A somatic second hit may be required for focal cyst development. although there is widespread immunohistochemical evidence of polycystin expression in cystic epithelia, Disruption of the mouse Pkd1 gene leads to death in the perinatal period with massive cystic expansion in homozygotes and age-related cyst development in heterozygotes. Normal renal development in Pkd1(del34/del34) mice up to embryonic day ~ 15.5 suggests a role for polycystin-1 in developing and maintaining the tubular architecture, consistent with the localization of the protein, rather than nephron induction. Renal cystic disease in homo- and heterozygotes of a Pkd2 mouse model with a disrupted exon 1 inserted in tandem with the normal exon (and prone to somatic recombination, which inactivates the gene) supports a role for somatic events in cystogenesis.

Original languageEnglish (US)
Pages (from-to)1861-1866
Number of pages6
JournalHuman Molecular Genetics
Volume8
Issue number10
DOIs
StatePublished - 1999
Externally publishedYes

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TRPP Cation Channels
Autosomal Dominant Polycystic Kidney
Homozygote
Heterozygote
Genes
Cysts
Exons
Proteins
Cystic Kidney Diseases
Transient Receptor Potential Channels
Kidney
Mutation
Nephrons
Ion Transport
Pedigree
Cell Communication
Genetic Recombination
Cues
Membrane Proteins
Epithelium

ASJC Scopus subject areas

  • Genetics

Cite this

Autosomal dominant polycystic kidney disease : Clues to pathogenesis. / Harris, Peter C.

In: Human Molecular Genetics, Vol. 8, No. 10, 1999, p. 1861-1866.

Research output: Contribution to journalArticle

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