Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) [Q61.2 ]

OMIM numbers: 173900601313 (PKD1), 613095, 173910 (PKD2)

Dr. rer. nat. Karin Mayer

Scientific Background

The autosomal dominant form of polycystic kidney disease (ADPKD, incidence approx. 1 in 1,000) is characterized by progressive development of fluid-filled cysts in all regions of the nephrons and collecting ducts as well as the formation of bilaterally enlarged, polycystic kidneys. The disease may already manifest during childhood and is marked by hematuria, high blood pressure and infection of the renal cysts. Many patients suffer from renal insufficiency between the 30th and 70th year of life which, in 50% of all patients, results in renal failure by the age of 60. About 95% of all patients have a positive family history.

The molecular cause of the disease is mutations in the PKD1 (85% of all cases) and the PKD2 gene (15% of all cases). In PKD1 mutation carriers, the disease manifests at a younger age, and renal failure occurs on average 20 years earlier than in carriers of PKD2 mutations (genotype-phenotype correlation). The PKD1 gene comprises 46 exons. A duplication of the exons 1-32 in form of a pseudogene (in total 6 copies) is located in a region further proximal on chromosome 16. The PKD2 gene comprises 15 exons. The point mutations identified so far in both genes contain all types of mutations and are spread over all exons. Genomic deletions are relatively rare and occur with a frequency of 4% in PKD1 and less than 1% in PKD2. The TSC2/PKD1 contiguous gene syndrome, in which large genomic deletions comprise PKD1 as well as the neighboring TSC2 gene, is an exception. These patients, however, show clinical signs and symptoms of tuberous sclerosis with early manifestation of renal cysts. These microdeletions can be detected using FISH. The sensitivity of mutation analysis for PKD1 and PKD2 is 75-90% in patients who fulfill the clinical criteria for ADPKD.

The gene products (polycystin-1 and 2) are transmembrane glycoproteins of the primary cilia of the renal epithelial cells and interact with each other through their cytoplasmic C terminal domain. Through various signal transduction cascades, the polycstin-1/polycystin-2 complex is involved in proliferation, apoptosis, differentiation as well as the regulation of cell shape and diameter of the renal tubules. The cysts develop according to the two-hit model: along with the germ line mutation in one of the two genes, a second, somatic mutation event in the same or the other PKD gene (trans-heterozygosity) inactivates the tumor suppressor function of both proteins (loss of heterozygosity, LOH).