Human Molecular Genetics, 1999, Vol. 8, No. 10 1861-1866
© 1999 Oxford University Press
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Autosomal dominant polycystickidney disease: clues to pathogenesis
MRC Molecular Haematology Unit, Institute of Molecular Medicine,John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
ABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD)is caused by mutation of one of two genes: PKD1 (16p13.3) or PKD2 (4q13–23). PKD1 accountsfor ~85% of pedigrees and is associated with significantlymore severe cystic disease. The ADPKD genes encode proteins, polycystin-1and polycystin-2, which are very different in size and structure,but which have a region of homology and may interact as part ofthe same complex. Polycystin-1 is a large, integral membrane protein(~460 kDa) predicted to be involved in cell–celland/or cell–matrix interactions. Polycystin-2(~110 kDa) is related to polycystin-1 and voltage-activated andtransient receptor potential channel subunits, suggesting that thepolycystins may also be associated with ion transport. A polycystincomplex could regulate cellular events (that are abnormal in ADPKD)in response to specific extracellular cues, mediated by controllingcellular Ca2+ levels and/or other signallingpathways. Recently, two further polycystin-like molecules have beenidentified, indicating roles for this novel protein family beyondthe kidney. A wide range of different mutations to the PKD1 or PKD2 gene have been detected, most predicted totruncate and inactivate the proteins. A somatic second hit may be requiredfor focal cyst development, although there is widespread immunohistochemicalevidence of polycystin expression in cystic epithelia. Disruptionof the mouse Pkd1 gene leads to death in the perinatalperiod with massive cystic expansion in homozygotes and age-relatedcyst development in heterozygotes. Normal renal development in Pkd1del34/del34 miceup to embryonic day ~15.5 suggests a role for polycystin-1 in developingand maintaining the tubular architecture, consistent with the localizationof the protein, rather than nephron induction. Renal cystic diseasein homo- and heterozygotes of a Pkd2 mouse model with a disruptedexon 1 inserted in tandem with the normal exon (and prone to somaticrecombination, which inactivates the gene) supports a role for somaticevents in cystogenesis.
FOOTNOTES
a Tel: +441865 222 391; Fax: +44 1865 222 500; Email: peter{at}hammer.imm.ox.ac.uk
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