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The role of the polycystins in kidney development
1Department of Medicine, Columbia University, New York, NY 10032, USA. jsv1@columbia.edu
Insights
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder. Mutations in PKD1 and PKD2 genes cause ADPKD, impacting fetal development and suggesting a role in morphoregulation.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic disorder affecting multiple organs.
- Key features include renal and extra-renal cysts, cardiac abnormalities, and arterial aneurysms.
- ADPKD is primarily caused by mutations in the PKD1 and PKD2 genes.
Purpose of the Study:
- To investigate the function and interaction of polycystin-1 and polycystin-2 proteins.
- To understand the genetic basis of ADPKD and its developmental implications.
- To explore the potential role of PKD genes in morphoregulatory pathways.
Main Methods:
- Gene cloning and sequencing of PKD1 and PKD2.
- Analysis of protein structures and predicted functions (receptor, calcium channel subunits).
- Comparative analysis of disease phenotypes in PKD1 and PKD2 mutation patients.
- Generation and analysis of genetically modified mouse models (PKD1/PKD2 knockout).
Main Results:
- PKD1 and PKD2 encode polycystin-1 and polycystin-2, respectively, with structural similarities to receptors and calcium channel subunits.
- Mutations in PKD1 or PKD2 lead to similar ADPKD phenotypes, with later onset in PKD2 cases.
- Evidence suggests polycystin-1 and polycystin-2 interact, explaining phenotypic similarities.
- Targeted mutations in PKD1 or PKD2 genes result in embryonic lethality in mice, indicating essential roles in fetal development.
Conclusions:
- PKD1 and PKD2 are crucial for normal embryonic development.
- The interaction between polycystins provides a molecular basis for ADPKD.
- PKD genes may function within a critical morphoregulatory pathway during development.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease that affects both adults and children. Renal cysts are the cardinal sign of the disease that also causes cysts in liver, pancreas, testis, and ovary, as well as cardiac valvular insufficiency and arterial aneurysms. At least three genes cause ADPKD in humans. PKD1 and PKD2 have been cloned and sequenced, both code for novel proteins. Analyses of their primary structures suggest that polycystin-1, the PKD1 gene product, is a receptor, while similarities between the polycystins and calcium channel subunits suggest that these proteins are subunits of a novel channel. Individuals with mutations in PKD1 or PKD2 have identical phenotypes, which present at a later age in PKD2 patients. Recent evidence suggests that the two polycystins interact, providing a biochemical basis for the similarity of disease caused by mutations in PKD1 and PKD2. Consistent with its protean manifestations, polycystin-1 is widely expressed in both epithelial and nonepithelial tissues during embryological development. Mice with targeted mutations of either the PKD1 or the PKD2 genes die during embryogenesis. Thus, the PKD genes are required for normal fetal development. The observation that loss of polycystin-1 or -2 function causes death during embryogenesis suggests that PKD1 and PKD2 might be part of a morphoregulatory pathway.