Genetics and Pathogenesis of Polycystic Kidney Disease (2002)

Polycystic kidney disease (PKD), a common genetic cause of chronic renal failure in children and adults, is characterized by the accumulation of fluid-filled cysts in the kidney and other organs. The renal cysts originate from the epithelia of the nephrons and renal collecting system and are lined by a single layer of cells that have higher rates of cellular proliferation and are less differentiated than normal tubular cells (1). Abnormalities in gene expression, cell polarity, fluid secretion, apoptosis, and extracellular matrix have also been described in PKD, but the mechanism of cyst formation remains incompletely understood (2–6). In recent months, there have been several advances in our understanding of the genetics and pathogenesis of PKD. Genes responsible for autosomal recessive PKD in humans and mice have been cloned, the PKD2 gene product has been identified as an intracellular calcium release channel, the PKD1 gene product has been found to regulate the cell cycle, and a neglected cellular organelle, the primary cilium, has emerged as a potential key player in polycystic disease. In this review, we will discuss how the cloning of the human PKD genes and the characterization of animal models have provided new insights into the pathogenesis of PKD. It is hoped that a more thorough understanding of the genetics and pathogenesis of PKD will lead to improvements in diagnosis and treatment. PKD can be inherited as an autosomal dominant trait (ADPKD) or an autosomal recessive trait (ARPKD) (Table 1). ADPKD is a common disease that occurs in both children and adults, whereas ARPKD is uncommon and occurs primarily in neonates and children. ADPKD is caused by mutations of either the PKD1 gene on chromosome 16 or the PKD2 gene on chromosome 4. The gene responsible for ARPKD (PKHD1) has recently been identified on chromosome 6. Renal cysts can also occur in association with other genetic diseases (e.g., tuberous sclerosis, von Hippel-Lindau disease, Zellweger syndrome, juvenile nephronophthisis), but these entities will not be discussed further here.Table 1: Characteristics of autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD)Autosomal Dominant Polycystic Kidney Disease ADPKD is one of the most common genetic diseases in humans affecting all ethnic groups worldwide with an incidence of 1 in 500 to 1 in 1,000 (7). The clinical manifestations include abdominal mass, chronic flank or back pain, gross hematuria, urinary tract infection, and urolithiasis. Affected individuals typically present in the third and fourth decade, and ESRD usually occurs within 5 to 10 yr after the development of renal insufficiency. However, presentation in infancy or childhood has also been reported (8,9). In addition to causing progressive renal failure, renal cysts can be complicated by hemorrhage, rupture, infection, nephrolithiasis, and intractable pain. Systemic hypertension is also very common, occurring in more than 75% of patients. Increased BP has been attributed to activation of the renin-angiotensin system, but a primary defect in blood vessels may also exist (10,11). Although ADPKD is characterized by kidney cysts and renal failure, it should be regarded as a systemic disease. The genes responsible for ADPKD are widely expressed, and mutations can affect a variety of extrarenal tissues (12). Cysts can arise in other epithelial organs, including the liver (75% of patients), pancreas (rare), ovaries, and choroid plexus. The liver cysts originate from the bile ducts and can become infected or hemorrhage but do not cause liver failure; cystic enlargement of the livers can produce symptoms due to mass effects. Other extrarenal manifestations include cerebral and aortic aneurysms, cerebral dolichoectasis, and colonic diverticuli. Cardiac valvular abnormalities include mitral valve prolapse, mitral regurgitation, aortic insufficiency, and tricuspid regurgitation. Left ventricular hypertrophy is common and has been observed in normotensive individuals. A striking feature of ADPKD is the variability of the phenotype. ADPKD is fully penetrant, meaning that virtually 100% of individuals who inherit a mutated PKD gene will develop renal cysts that can be detected sonographically by age 30 (13). However, the severity of the disease, the age of onset of ESRD, and the spectrum of extrarenal manifestations vary widely between affected individuals, even within the same family (14). Possible explanations for the variable expressivity of the disease are discussed below. Genetics of ADPKD ADPKD is genetically heterogeneous and can arise from mutations in two genes, named PKD1 and PKD2 (15,16). Mutations of PKD1 located on chromosome 16p13.3 are responsible for 85% of cases, whereas mutations of PKD2 on chromosome 4q21–23 are responsible for 15% of cases. In elderly patients, mutations of PKD2 are responsible for a higher percentage of cases. Forty percent of PKD patients presenting with ESRD after age 63 have disease linked to PKD2, and the rate is 50 to 70% in patients presenting with ESRD after age 70 (17,18). Mutations of PKD1 and PKD2 produce identical renal and extrarenal manifestations. However, compared with PKD1 patients, PKD2 patients present later in life (median age at diagnosis, 56 versus 42), have longer renal survival (median survival to age 69 versus 53), and have fewer complications (19). Only 5% of cases due to mutations of PKD1 are thought to represent new mutations (20). Some families were initially reported to have PKD that is apparently not linked to either PKD1 or PKD2, but recent confirmation of these findings is lacking. One such family actually had bilineal inheritance of both PKD1 and PKD2 mutations (21). The PKD1 gene is very large, consisting of 46 exons distributed over 52 kb of genomic DNA (22,23). The gene encodes a 14.1-kb mRNA transcript that is translated into a protein composed of 4302 amino acids. Interestingly, the region of the gene extending from exon 1 to exon 33 is duplicated at six other sites on chromosome 16p. The duplicated genes are expressed as mRNA transcripts and may represent pseudogenes (24). Their existence has hindered mutational analysis because it can be difficult to distinguish mutations of PKD1 from mutations of the duplicated genes. More recently, with the use of long-range PCR, denaturing HPLC (DHPLC), and the protein truncation test, mutations in the duplicated region of the PKD1 gene have been identified (20,25,26). Rossetti et al. (20) have recently completed the most comprehensive survey of PKD1 mutations to date. Unlike cystic fibrosis, in which a single mutation of CFTR occurs in 70% of affected individuals, mutations of PKD1 can be found throughout the gene. Different types of mutations have been observed including splice site, in-frame, and out-of-frame deletions and insertions, nonsense mutations, and missense mutations. The out-of-frame deletions/insertions and nonsense mutations are very likely to represent inactivating mutations. No correlations between specific mutations and specific clinical manifestations have been identified, but mutations in the 5′ end of the gene appear to be associated with earlier onset disease than mutations in the 3′ end (27). The second ADPKD gene, PKD2, was cloned in 1996 by positional cloning (28). The PKD2 gene is located on chromosome 4q21–23 and encodes a 5.3-kb mRNA transcript that is translated into a 968 amino acid protein. PKD2 is approximately 25% homologous to a region of the PKD1 gene. Patients with ADPKD linked to chromosome 4 are heterozygous for inactivating mutations of PKD2, proving that PKD2 is the disease gene (18,28). Mutations have been identified throughout the gene without evidence for clustering (29). Most of the mutations identified to date are truncating mutations (frameshift, splicing, or nonsense mutations) that would be predicted to inactivate the gene product. Only 5% of mutations are missense mutations. The location of mutations in the gene has been reported to have a nonlinear relationship to clinical severity (30). Unlike PKD1, the PKD2 gene is not duplicated, which has simplified the mutational analysis. ADPKD is a Focal Disease In a landmark study, Luc Baert (31) microdissected the kidneys of young adults with ADPKD at an early stage of the disease, when the source and extent of the cysts be that cysts arise from the tubular of the as as the renal collecting However, all cells of the the same a cysts arise nephrons appear ADPKD is a disease that a of cells in the even all cells one of the mutated gene. the of as as the variable expressivity a of has been In this a mutated PKD1 gene is inherited from one and a gene is inherited from the the of the the gene a mutation and of PKD1 in cells in which second mutations have cyst mutations are and will occur in a of the formation of cysts will be have that renal cysts from ADPKD patients of due to of the a of the of inheritance is the disease occurs by a recessive In renal cysts are with an from a single cell that has a mutation mutations of the PKD1 and PKD2 genes have been identified in the cells the cysts in both the kidney and liver renal cyst from a second a rate of would be to the of cysts that are found in polycystic that the rate of mutations in kidney epithelial cells is approximately which is more than higher than in other cells The for the rate of in the kidney is not of the is that mutations of PKD1 and PKD2 would be more than heterozygous mutations. humans with mutations of either PKD1 or PKD2 have been because is of the human PKD1 and PKD2 genes exist in the and mice that one or both of the and genes have been mice develop cysts in the kidney or liver in whereas mice are and develop cystic kidneys in Kidney development when cysts to appear the the kidneys are with that the cysts arise from all of the and the renal collecting that of or is to cause renal cysts and the evidence from a of mice a that is to genomic The protein. However, life it can to produce either a or a that the develop cysts in the kidney and with an to the gene product in but not in the cyst the gene is in cyst epithelial cells and the heterozygous mice represent the most animal of human ADPKD to date. Although the of the disease, other genetic such as or mutations, have not been and are likely to be it has been that cysts can have mutations in which individuals that a mutation of PKD1 a second that the other ADPKD gene, PKD2 individuals mutations of PKD2 can have cysts in which there are mutations of PKD1 with mutations of and more renal cystic disease than would be predicted by a of the cyst formation in heterozygous mice that of both PKD1 and PKD2 may also a in cyst The by the PKD1 and PKD2 genes a new the which in a variety of including and the product of the PKD1 gene, 4302 amino and has a of in is an protein that is predicted to The large, extracellular a of protein including two by a a and 16 PKD of these are in or which the that may as a for an as to the there is a region of to the and a potential the and second there is a region of to The of is located in the and a that as as several potential sites of of and the extracellular or are identified in the represent Only the of is are not to is expressed in including the and The of has been However, several have identified in the of tubular epithelial in the and collecting ducts In it is primarily in the at sites of with these has been identified in cell including and is and in two one is to and which is associated with the is Although the of is not is to a family of cell that are in the an in The is an in which a within the with the and into the extracellular The is by the of a in the the to the on the of the in calcium and and in The from and were found to be homologous to that are between and one or more include the and PKD The with the that may also be a cell and that the may be in this is the of at the in a the that at the in has a in in the kidney as a for in in cells has recently been that is to the of is the and in are for the by a of In the appear to as and in as as intracellular has recent in the of the in kidneys The of has been to a of intracellular of the the of and activation of Interestingly, one of the for activation by this to be the PKD1 gene The of is in an that is by the of have that protein The of can and the of A recent has that as a that and this is of but is by protein regulate that are in cyst such as fluid secretion, cell polarity, and also appear to be in activation of and A feature of cyst epithelial cells is an rate of cellular proliferation of in cells cellular proliferation and cyst formation In a recent study, et al. have that has a in the of the cell by cell at the the cell is by and it was found that by the in a that and that to activation of The PKD2 gene encodes a that is composed of 968 amino (28). is predicted to be an protein. six and intracellular and 1). The of are identical to the of the of also with potential as as calcium and The a as an that can is widely expressed in the and In the is expressed in all with the of the but is from The of that it as an channel, and single as as have that is a that can calcium to the of have been provided by types of both in and in have that with The of a that to the of and of the of either protein this The in of this is by the that and in the same genetic in In the of with protein and in a common would mutations of either PKD1 or PKD2 produce diseases with identical clinical manifestations. whereas to be located in the the of is located in primarily the The is by the of to with and by that it with in both cells and kidney A that in the has been identified in the 1). and with have been to from the and to the cell in cells recent on in cells have found the protein in the and at the In cells as a with both an and an of the is associated with the and of that the can be on the cell whereas several have that the including calcium and that this can be by calcium on the A recent further that can calcium release from intracellular in to that calcium A occurring human disease mutation a amino acid in the third in of without apparently the and of the protein these that in and that the of the to calcium in of to cause polycystic kidney disease. The of and several that are in In is in the with in the relationship is of between in the and in the may as a for an as extracellular and to the cell with The in activation of calcium and in calcium that and in gene A defect in has been observed in cyst epithelial cells and may be responsible for the of to the that has been found in PKD In both and are in the of to activation of which of extracellular a in that as a that and of protein may regulate fluid secretion, cell polarity, and that activation of to activation of in a of of of and cell at the of is located in the and a with which is primarily found in the of by an as to activation of an that calcium from the into the of calcium from the in the that calcium further The in calcium that lead to and in gene sites both and are located in the activation of to activation of and calcium the The in calcium to and in gene of protein by and (1). of and release of the of and other that regulate fluid secretion, cell polarity, and The of with the of protein of the by of to activation of in a and which that to the and to the gene of the which to cell in Polycystic Kidney Disease (ARPKD) ARPKD is less common than ADPKD and occurs in 1 in to 1 in (Table ARPKD is characterized by the of renal cystic disease and The renal cystic disease typically in and as of the collecting ducts that from the to the cysts also appear in The renal cystic disease is associated with which is a characterized by bile ducts and cystic of the bile ducts is in the to of patients with disease of the pancreas has also been described in patients the clinical presentation of ARPKD is ARPKD can present as or disease The variability in the age of onset is due to variable of mutations of the same gene as as the of genes and than mutations of genes variability is less than variability between families The of ARPKD at with kidneys and renal from and to 30 to of affected after due to or failure who do not present after the of life have less cystic and a The renal cysts are and than in the and may which can be by analysis or renal of the who the have a 56 to of survival to age without ESRD, and survival to age has been reported However, develop of hypertension including and Other clinical manifestations of ARPKD in children and adults include systemic hypertension to 70% of patients), urinary tract infection, and Patients with disease may develop complications of and of the ARPKD (PKHD1) cases of ARPKD are due to mutations of the gene on chromosome to chromosome was in and genetic and the gene to a this groups cloned the gene in the region on chromosome et al. a of to a region on chromosome that was with the ARPKD region on human chromosome analysis identified a gene (PKHD1) that was mutated in both the and in humans with et al. cloned the identical gene by a of the ARPKD region and a transcript that was expressed in the of this gene identified mutations found in affected individuals and with the disease in affected et al. have also recently reported the of the human ARPKD gene and the on chromosome these that the gene responsible for ARPKD has been The gene is very and of at exons extending over kb of genomic DNA The gene a of to mRNA transcripts in from kb to with the sites affected by the disease, the gene is expressed at in the and kidney and at in the liver and In the is expressed in renal as as in the bile blood and Mutations of that have been identified in patients include and out-of-frame that are with a In an of missense the of which are less have also been found Most individuals in two mutations have been identified are with one mutation and one predicted missense or two predicted missense In the one with two mutations has been identified, that the disease may from of the gene product are to there is relationship between the of the mutations and the clinical of the disease. The protein by the gene has been named or and is composed of amino is predicted to be a protein consisting of a extracellular a single and a A splice that encodes a protein the has also been identified and may a of the protein is a it has to other in the The is to a protein of from of the predicted amino acid of identified a at the amino The extracellular six to which are that have been identified in cell such as the and as as in the family of the and the there are to 10 which are also found in potential protein A sites were identified in the The of that it may be a cell or with will be to the and of and to how mutations of the protein cause disease. PKD a are tubular that are present on the of most cells of a that is with the cell and a that is composed of originate from the an intracellular to the are as primary or The of primary of whereas the of such as in and two as as Renal tubular epithelial cells 1 to primary that have a have been identified in all of the from to collecting ducts with the of cells The primary in the kidney are to 10 in and from the cell into the Some primary are such as in the but in the kidney are thought to be primary may have a or Although existence has been for more than a primary were However, recent that of primary may produce polycystic kidney of primary are tubular of the cell that are composed of an by the The of in a and from the end of the The of and is to the which is in of by the the product of the gene mutated in is a of the and is distributed in the and the which is mutated in is located in the and may be to the by an and have also recently been identified in renal that of renal in to a in of in PKD was by of the which is a of ARPKD that was by mice develop renal collecting and and usually within the of The gene that is mutated in mice encodes a named which that may be in is expressed in cells and to the and Most cells in the kidney and the protein has also been to the primary of In the primary in the renal collecting ducts are The of has been by of homologous in the and the In the named is expressed in the of that are in that and are to due to The the to develop was by in which that are to have that the and of and a as to the of or that are thought to from the of the to the The that are by are composed of at one of named is homologous to mutations of have that is also to and is for in and kidney cells that mutations of the of primary in kidney and that this to polycystic kidney disease. Interestingly, mice in to develop due to in the formation of in early with in the is in that it renal cysts in addition to abnormalities of of the gene not the defect in but also the renal cystic abnormalities of including and have also been observed in mice The of of with kidney cysts in several models to the that may a in renal cystic disease. The of in PKD is further by of the which is a occurring recessive of polycystic kidney disease mice develop kidney cysts in and to renal failure within 4 to 5 after et al. identified the gene by positional cloning and found that it encodes a acid protein that is expressed primarily in the kidney and which named The of is and not to in the However, the protein two potential sites that it in the is expressed in collecting the protein to the primary higher can be found the but not appear to be expressed in the from which the the and models to the potential of in are in may also be in the pathogenesis of autosomal dominant PKD. of and have been identified in named location of and also appear to be for the of and to the of the same that is also expressed in a in the cell with in the with with mutations of the and genes due to have a and of not that the two genes in the same In the are and and in the In and the of the to be normal that these genes are not for et al. have identified in the primary of renal epithelial In addition to in the with in the of and human kidney in renal is also in kidney In mice that have renal and polycystic kidney disease, the of in the is in which and are of the of and with an in et al. have that is also expressed in renal it with further the that abnormalities of a in the pathogenesis of PKD. is not it is not how abnormalities of renal would produce kidney in the kidneys of are and are thought to However, the of primary in the kidney not a Other that have been include of of for a urinary and of urinary In of the primary in renal epithelial cells have been to in to of the in either or with a in intracellular calcium that the in the kidney may as of to the of in are to the normal of renal and how in and lead to cyst as for of PKD No specific for PKD it is hoped that a more understanding of the pathogenesis of the disease will the potential of was et al. of in the of such as the of and is an in of mice with the of PKD and Some more than with treatment. Other also cyst and the of these are to to in Other have these the to be specific to mice are with the that of in at is to affect the defect for the in the the other the of in ADPKD is and is to the in the of of that are at the a in the most common of that caused by mutations in by the of Kidney Disease and the for the of Polycystic Kidney Disease of this were at on