Related Experiment Videos
Autosomal dominant polycystic kidney disease: clues to pathogenesis
1MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK. peter@hammer.imm.ox.ac.uk
Insights
Autosomal dominant polycystic kidney disease (ADPKD) arises from mutations in PKD1 or PKD2 genes, affecting polycystin proteins crucial for kidney development and function. Mouse models reveal polycystin disruption causes severe cystic kidney disease, highlighting its role in tubular architecture maintenance.
Area of Science:
- Genetics and Molecular Biology
- Nephrology
- Cell Biology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder caused by mutations in either the PKD1 or PKD2 gene.
- PKD1 mutations, accounting for ~85% of cases, are linked to more severe cystic disease.
- The PKD1 and PKD2 genes encode polycystin-1 and polycystin-2, proteins potentially interacting in a complex involved in cellular signaling and ion transport.
Purpose of the Study:
- To investigate the genetic basis and protein functions underlying ADPKD.
- To explore the role of polycystins in kidney development and cystogenesis.
- To understand the implications of different mutations in PKD1 and PKD2.
Main Methods:
- Analysis of PKD1 and PKD2 gene mutations.
- Immunohistochemical studies of polycystin expression in cystic epithelia.
- Generation and analysis of Pkd1 and Pkd2 knockout mouse models.
Main Results:
- Disruption of Pkd1 in mice leads to perinatal death with severe cystic kidneys in homozygotes and age-related cyst development in heterozygotes.
- Pkd1 disruption affects tubular architecture maintenance, not initial nephron induction.
- Pkd2 mouse models also exhibit renal cystic disease, supporting a role for somatic events in cyst formation.
Conclusions:
- Polycystin-1 and polycystin-2 play critical roles in maintaining kidney tubular structure.
- Mutations in PKD1 and PKD2 disrupt polycystin function, leading to ADPKD.
- Somatic events may contribute to the focal development of cysts in ADPKD.
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 approximately 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 ( approximately 460 kDa) predicted to be involved in cell-cell and/or cell-matrix interactions. Polycystin-2 ( approximately 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 approximately 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.