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Polycystic kidney disease (PKD) is caused by mutations in the genome, mostly inherited (90%) but occasionally sporadic.
In the great majority of individuals with PKD, the condition is inherited in an autosomal dominant manner, known as autosomal dominant polycystic kidney disease (ARPKD). This is due to mutations in the PKD1 gene on chromosome 16, causing type 1 disease. This accounts for more than 85% of cases. In most of the remaining, the mutation is in the PKD2 gene on chromosome 4, which results in type 2 ADPKD.
These genes code for proteins called polycystin 1 and polycystin 2 respectively. Type 2 ADPKD is typically milder in course, with delayed onset of renal insufficiency, especially when it occurs in women.
95% of patients have a parent with the disease but in a tenth of families the mutation arose de novo.
The overall incidence of the mutant gene in ADPKD is up to 1/400 individuals and it is transmitted to 50% of offspring. One copy of the defective gene is sufficient to produce the clinical syndrome. In addition, if one abnormal copy of both genes is present, the clinical course may be more severe and progress more rapidly than if only one gene was abnormal.
Since the cysts grow at the same rate in both forms, it is likely that the difference is due to a higher number of cysts in type 1, rather than a higher growth rate. Other genes may also be involved in determining the manifestations of the disease. Every generation is likely to have affected individuals because of the dominant character of the inherited trait.
Polycystin 1 is a regulator of tubular epithelial cell adhesion and differentiation. Polycystin 2 is an ion channel. Mutations in these genes lead to dysfunction of the cilia on the tubular epithelium. Ciliary function is critical in helping the cells determine the rate of flow of urinary fluid. In the absence of the functional protein, tubular cells fail to sense this information, causing a deficit in their proliferation and differentiation and eventual transformation of the tubule into a cyst.
Early in the course of the disease, the tubules start to dilate, and are filled with ultrafiltered fluid from the glomeruli. With increasing cystic change, they detach from the parent glomeruli and transform into full-grown cysts, secreting still more fluid, leading to cyst enlargement.
Mutations in the PKHD1 are responsible for causing autosomal recessive polycystic kidney disease (ARPKD). This condition is much less frequent and occurs in only 1/10000 to 1/20000 individuals. It is carried via two copies of the abnormal PKHD1 gene on chromosome 6, one from each parent. Thus each child has a 25% chance of inheriting the disease, a 50% chance of being a carrier (having one copy of the gene, without clinical expression) and a 25% chance of not inheriting the abnormal gene at all. In this case, generations may be skipped with respect to the expression of the trait, because of its recessive character. Thus having early-onset polycystic kidney disease without a family history is suggestive of the ARPKD form, because the parents are carriers but not affected by the phenotypic expression of cyst formation.
The PKHD1 gene is found to occur in the kidneys, biliary ducts and the pancreas and is responsible for the expression of the protein fibrocystin. It is linked to cilia as well as to other sites in the tubular epithelium. Ciliary dysfunction due to the absence or low functional status of fibrocystin, leading to proliferation and secretory change in the affected tubular cells is thought to be the mechanism of cystic transformation.