Molecular Advances in Autosomal Dominant Polycystic Kidney Disease
2010; Elsevier BV; Volume: 17; Issue: 2 Linguagem: Inglês
10.1053/j.ackd.2010.01.002
ISSN1548-5609
AutoresAnna‐Rachel Gallagher, Gregory G. Germino, Stefan Somlo,
Tópico(s)Genetic Syndromes and Imprinting
ResumoAutosomal dominant polycystic disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. The understanding of the pathogenesis of ADPKD has advanced significantly since the discovery of the 2 causative genes, PKD1 and PKD2. Dominantly inherited gene mutations followed by somatic second-hit mutations inactivating the normal copy of the respective gene result in renal tubular cyst formation that deforms the kidney and eventually impairs its function. The respective gene products, polycystin-1 and polycystin-2, work together in a common cellular pathway. Polycystin-1, a large receptor molecule, forms a receptor-channel complex with polycystin-2, which is a cation channel belonging to the TRP family. Both polycystin proteins have been localized to the primary cilium, a nonmotile microtubule-based structure that extends from the apical membrane of tubular cells into the lumen. Here we discuss recent insights in the pathogenesis of ADPKD including the genetics of ADPKD, the properties of the respective polycystin proteins, the role of cilia, and some cell-signaling pathways that have been implicated in the pathways related to PKD1 and PKD2. Autosomal dominant polycystic disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. The understanding of the pathogenesis of ADPKD has advanced significantly since the discovery of the 2 causative genes, PKD1 and PKD2. Dominantly inherited gene mutations followed by somatic second-hit mutations inactivating the normal copy of the respective gene result in renal tubular cyst formation that deforms the kidney and eventually impairs its function. The respective gene products, polycystin-1 and polycystin-2, work together in a common cellular pathway. Polycystin-1, a large receptor molecule, forms a receptor-channel complex with polycystin-2, which is a cation channel belonging to the TRP family. Both polycystin proteins have been localized to the primary cilium, a nonmotile microtubule-based structure that extends from the apical membrane of tubular cells into the lumen. Here we discuss recent insights in the pathogenesis of ADPKD including the genetics of ADPKD, the properties of the respective polycystin proteins, the role of cilia, and some cell-signaling pathways that have been implicated in the pathways related to PKD1 and PKD2. Autosomal dominant polycystic kidney disease (ADPKD; MIM 173900) is a systemic disorder characterized by age-dependent occurrence of bilateral, multiple renal cysts as well as a variety of extrarenal manifestations. The latter include cysts in the liver bile ducts, pancreatic ducts, seminal vesicles, and arachnoid membrane as well as noncystic manifestations, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, and abdominal wall hernias.1Torres V.E. Harris P.C. Pirson Y. Autosomal dominant polycystic kidney disease.Lancet. 2007; 369: 1287-1301Abstract Full Text Full Text PDF PubMed Scopus (845) Google Scholar The study of this disease through human genetics, animal models, classic cell biology, and biochemical approaches has yielded remarkable insights; however, the goal of finding an effective treatment is still a work in progress. Mutations in 2 genes, PKD1 and PKD2, are responsible for ADPKD.2The European Polycystic Kidney Disease ConsortiumThe polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16.Cell. 1994; 78: 725Abstract Full Text PDF Scopus (214) Google Scholar, 3The International Polycystic Kidney Disease ConsortiumPolycystic kidney disease: The complete structure of the PKD1 gene and its protein.Cell. 1995; 81: 289-298Abstract Full Text PDF PubMed Scopus (591) Google Scholar, 4Mochizuki T. Wu G. Hayashi T. et al.PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1072) Google Scholar Subsequently, the genes for a number of other inherited diseases that manifest with varying degrees of cyst formation (eg, recessive polycystic kidney disease, nephronophthisis, Bardet Biedl syndrome, and several others) have been discovered.5Onuchic L.F. Furu L. Nagasawa Y. et al.PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats.Am J Hum Genet. 2002; 70: 1305-1317Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar, 6Ward C.J. Mc Hogan Rossetti S. et al.The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein.Nat Genet. 2002; 30: 259-269Crossref PubMed Scopus (533) Google Scholar, 7Hildebrandt F. Attanasio M. Otto E. Nephronophthisis: Disease mechanisms of a ciliopathy.J. Am Soc Nephrol. 2009; 20: 23-35Crossref PubMed Scopus (235) Google Scholar, 8Zaghloul N.A. Katsanis N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy.J Clin Invest. 2009; 119: 428-437Crossref PubMed Scopus (263) Google Scholar Mechanistic studies of ADPKD and the other cystic kidney diseases have identified a previously little appreciated organelle, the primary cilium, and its associated basal body complex as the central cellular compartment in the pathogenesis of this group of disorders.9Guay-Woodford L.M. Renal cystic diseases: Diverse phenotypes converge on the cilium/centrosome complex.Pediatr. Nephrol. 2006; 21: 1369-1376Crossref PubMed Scopus (36) Google Scholar These insights have accelerated a broader understanding of the clinical diseases and have moved the field to the threshold of directed therapeutic clinical trials for ADPKD. Mutations in at least 2 genes cause the clinical presentation of ADPKD. PKD1, located on chromosome 16p13.3, accounts for 85% of families; PKD2, on chromosome 4q21, accounts for the remainder (Table 1). Families with mutations in PKD1 tend to have more severe clinical presentations, but there is marked intrafamilial and interfamilial variability in the clinical manifestations of ADPKD that go beyond the germline mutation and may suggest a possible role for genetic background in disease progression.10Hateboer N. Lazarou L.P. Williams A.J. et al.Familial phenotype differences in PKD11.Kidney Int. 1999; 56: 34-40Crossref PubMed Scopus (52) Google Scholar, 11Milutinovic J. Rust P.F. Fialkow P.J. et al.Intrafamilial phenotypic expression of autosomal dominant polycystic kidney disease.Am J Kidney Dis. 1992; 19: 465-472Abstract Full Text PDF PubMed Scopus (56) Google Scholar, 12Persu A. Duyme M. 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Although it is likely that a complete loss of function mutations affecting either gene would result in nonviable progeny,16Pei Y. Paterson A.D. Wang K.R. et al.Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease.Am J Hum Genet. 2001; 68: 355-363Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 17Paterson A.D. Wang K.R. Lupea D. et al.Recurrent fetal loss associated with bilineal inheritance of type 1 autosomal dominant polycystic kidney disease.Am J Kidney Dis. 2002; 40: 16-20Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar a recent report described several individuals carrying 2 incompletely penetrant, hypomorphic, PKD1 mutations.18Rossetti S. Kubly V.J. Consugar M.B. et al.Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease.Kidney Int. 2009; 75: 848-855Crossref PubMed Scopus (174) Google ScholarTable 1Summary of ADPKD Gene and Protein CharacteristicsPKD1PKD2Mutations in ADPKD families85%15%Mean age of onset ESRD53 years69 yearsGene characteristicsChromosome 16q13.346 exons gene size, ~45 kbspliced transcript, ~12.9 kbChromosome 4q21-2315 exons gene size, ~50 kbspliced transcript, ~3.5 kbProtein characteristicsPolycystin 1 (PC1)4302 amino acids11 transmembrane domainsReceptor-like proteinUndergoes proteolytic cleavagePolycystin 2 (PC2; TRPP2)968 amino acids6 transmemebrane domainsHomology to TRP channelsSubcellular localizationCilia, cell junctions, apical and basolateral plasma membraneCilia, endoplasmic reticulum, plasma membraneFunctionReceptorCation channel Open table in a new tab PKD1 and PKD2, respectively, encode for proteins polycystin-1 (PC1) and polycystin-2 (PC2) (Fig 1). 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Larson C.H. et al.Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease.Dev Cell. 2006; 10: 57-69Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar Polycystin-2 (PC2) consists of 968 amino acids with 6 transmembrane domains.29Cai Y. Maeda Y. Cedzich A. et al.Identification and characterization of polycystin-2, the PKD2 gene product.J Biol Chem. 1999; 274: 28557-28565Crossref PubMed Scopus (276) Google Scholar It is a nonselective cation channel permeable to Ca2+ that belongs to the TRPP subfamily of TRP cation channels (TRPP230Nilius B. Owsianik G. Voets T. et al.Transient receptor potential cation channels in disease.Physiol Rev. 2007; 87: 165-217Crossref PubMed Scopus (1006) Google Scholar). The last 5 transmembrane spans in PC2 bear a strong TRP channel signature, and the region between S5 and S6 (transmembrane segments 5 and 6) contains the putative pore region (Fig 1).24Li A. 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