Emerging evidence of a link between the polycystins and the mTOR pathways

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Date: Oct. 28, 2009
From: PathoGenetics(Vol. 2)
Publisher: BioMed Central Ltd.
Document Type: Report
Length: 12,786 words

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Authors: Alessandra Boletta (corresponding author) [1]

ADPKD: genetics and proposed mechanisms of cystogenesis

Autosomal dominant polycystic kidney disease (ADPKD) is a frequent genetic disease, affecting between 1:500 and 1:1000 of the general population [1, 2, 3]. The hallmark of the disease is bilateral renal cyst formation, although a plethora of extra-renal manifestations have been reported. These include liver and pancreatic cysts as well as cardiovascular complications (for review of the clinical aspects of the disease, see [1]). Two genes have been linked to this disease: PKD1 , which is mutated in 85% of cases, and PKD2 , which is mutated in most of the remaining cases. Numerous mutations have been reported along the length of these two genes; most are loss-of-function mutations predicted to inactivate the affected allele [1, 2, 3].

Genetic mechanism of cystogenesis

ADPKD is inherited in an autosomal dominant manner, but it has been suggested that it is recessive at the molecular level [4]. Analysis of the epithelia derived from renal or liver cysts has revealed that the normal inherited allele undergoes a somatic mutation, resulting in homozygous loss of either the PKD1 or PKD2 gene [4, 5]. This 'second hit' causes a single affected epithelial cell to over-grow and generate a clonal outpouching diverticulum, which eventually disconnects from the renal tubule. In some of the cysts in which homozygous inactivation of one PKD gene (either 1 or 2) is not observed, mutations in the other PKD gene have been found, suggesting that trans-heterozygosity of the two genes is sufficient to induce cyst formation [6]. Based on these findings, a 'threshold model' of cystogenesis has been proposed, in which heterozygosity is not sufficient to induce renal cystogenesis, but a minimum level of activity of the PKD1 and PKD2 gene products, the polycystins, is required to prevent cystogenesis. Any dysfunction causing polycystin activity to fall below such a threshold would lead to cyst formation, even though a complete loss of function does not appear to be necessary. Several findings from studies in animal models appear to support this model: (i) heterozygosity of the Pkd1 or Pkd2 gene is not sufficient to cause renal cyst formation in mice, possibly due to a low rate of second hits in the murine kidney, whereas homozygous inactivation causes renal cystogenesis in utero [7, 8]; (ii) conditional inactivation of the second allele in the kidney results in renal cystogenesis with a variably severe phenotype depending on the time of inactivation [9, 10]; (iii) a mouse model carrying an unstable Pkd2 allele that spontaneously undergoes somatic inactivation displays the ADPKD phenotype when crossed with a Pkd2 -null mouse [11]; (iv) trans-heterozygous Pkd1 +/- :Pkd2 +/- mice display markedly more severe cystic kidney disease than single heterozygous mutants [12]; and (v) a mouse model carrying an aberrantly spliced variant of the Pkd1 gene, lowering its expression to 13-20% of normal levels, suffers renal cystogenesis [13].

Intriguingly, a recent study has identified ADPKD families carrying homozygous inheritance of mild mutations in the PKD1 gene, which resulted in PKD; this finding...

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Gale Document Number: GALE|A212816332