Somatic PKD2 Mutations in Individual Kidney and Liver Cysts Support a "Two-Hit" Model of Cystogenesis in Type 2 Autosomal Dominant Polycystic Kidney Disease
An intriguing feature of autosomal dominant polycystic kidney disease (ADPKD) is the focal and sporadic formation of renal and extrarenal cysts. Recent documentation of somatic PKD1 mutations in cystic epithelia of patients with germ-line PKD1 mutations suggests a "two-hit" model for cystogenesis in type 1 ADPKD. This study tests whether the same mechanism for cystogenesis might also occur in type 2 ADPKD. Genomic DNA was obtained from 54 kidney and liver cysts from three patients with known germ-line PKD2 mutations, using procedures that minimize contamination of cells from noncystic tissue. Using intragenic and microsatellite markers, these cyst samples were screened for loss of heterozygosity. The same samples were also screened for somatic mutations in five of the 15 exons in PKD2 by single-stranded conformational polymorphism analysis. Loss of heterozygosity was found in five cysts, and unique intragenic mutations were found in seven other cysts. In 11 of these 12 cysts, it was also determined that the somatic mutation occurred nonrandomly in the copy of PKD2 inherited from the unaffected parent. These findings support the "two-hit" model as a unified mechanism for cystogenesis in ADPKD. In this model, the requirement of a somatic mutation as the rate-limiting step for individual cyst formation has potential therapeutic implications.
Available from: Wybrich R Cnossen
- "This is the rate-limiting step in the formation of cysts. Secondary, somatic hit mutations have been identified in PKD1 or PKD2 genes in liver and kidney tissues from ADPKD patients [70,71]. Similarly, loss-of-heterozygosity of the PRKCSH or SEC63 allele is present in PCLD cyst tissues. "
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ABSTRACT: Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications. Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ. Renal failure due to polycystic kidneys and non-renal extra-hepatic features are common in ADPKD in contrast to VMC and PCLD. In general, liver function remains prolonged preserved in PLD. Ultrasonography is the first instrument to assess liver phenotype. Indeed, PCLD and ADPKD diagnostic criteria rely on detection of hepatorenal cystogenesis, and secondly a positive family history compatible with an autosomal dominant inheritance pattern. Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics. Screening mutations of the genes causing PCLD (PRKCSH and SEC63) or ADPKD (PKD1 and PKD2) confirm the clinical diagnosis. Genetic studies showed that accumulation of somatic hits in cyst epithelium determine the rate-limiting step for cyst formation. Management of adult PLD is based on liver phenotype, severity of clinical features and quality of life. Conservative treatment is recommended for the majority of PLD patients. The primary aim is to halt cyst growth to allow abdominal decompression and ameliorate symptoms. Invasive procedures are required in a selective patient group with advanced PCLD, ADPKD or liver failure. Pharmacological therapy by somatostatin analogues lead to beneficial outcome of PLD in terms of symptom relief and liver volume reduction.
Orphanet Journal of Rare Diseases 05/2014; 9(1):69. DOI:10.1186/1750-1172-9-69 · 3.36 Impact Factor
Available from: Zhousheng Xiao
- "In global knockout mice it is difficult to differentiate between indirect extra-renal abnormalities due to the effects of the complex metabolic alterations caused by renal cystic disease from direct effects caused by loss of Pkd1 functions in affected tissues. In addition, in humans, ADPKD is a heterozygous state, whereby mutations leading to loss of one PKD1 or PKD2 allele is combined with somatic mutations in the kidney (i.e., a second hit) to cause renal cystic disease , , , , . The resulting residual function of the non-mutated PKD1 or PKD2 allele in extra-renal tissues may also mask discovery of PKD1 or PKD2 functions in non-renal tissues. "
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ABSTRACT: Conditional deletion of Pkd1 in osteoblasts using either Osteocalcin(Oc)-Cre or Dmp1-Cre results in defective osteoblast-mediated postnatal bone formation and osteopenia. Pkd1 is also expressed in undifferentiated mesenchyme that gives rise to the osteoblast lineage. To examine the effects of Pkd1 on prenatal osteoblast development, we crossed Pkd1(flox/flox) and Col1a1(3.6)-Cre mice, which has been used to achieve selective inactivation of Pkd1 earlier in the osteoblast lineage. Control Pkd1(flox/flox) and Pkd1(flox/+), heterozygous Col1a1(3.6)-Cre;Pkd1(flox/+) and Pkd1(flox/null), and homozygous Col1a1(3.6)-Cre;Pkd1(flox/flox) and Col1a1(3.6)-Cre;Pkd1(flox/null) mice were analyzed at ages ranging from E14.5 to 8-weeks-old. Newborn Col1a1(3.6)-Cre;Pkd1(flox/null) mice exhibited defective skeletogenesis in association with a greater reduction in Pkd1 expression in bone. Conditional Col1a1(3.6)-Cre;Pkd1(flox/+) and Col1a1(3.6)-Cre;Pkd1(flox/flox) mice displayed a gene dose-dependent decrease in bone formation and increase in marrow fat at 6 weeks of age. Bone marrow stromal cell and primary osteoblast cultures from homozygous Col1a1(3.6)-Cre;Pkd1(flox/flox) mice showed increased proliferation, impaired osteoblast development and enhanced adipogenesis ex vivo. Unexpectedly, we found evidence for Col1a1(3.6)-Cre mediated deletion of Pkd1 in extraskeletal tissues in Col1a1(3.6)-Cre;Pkd1(flox/flox) mice. Deletion of Pkd1 in mesenchymal precursors resulted in pancreatic and renal, but not hepatic, cyst formation. The non-lethality of Col1a1(3.6)-Cre;Pkd1(flox/flox) mice establishes a new model to study abnormalities in bone development and cyst formation in pancreas and kidney caused by Pkd1 gene inactivation.
PLoS ONE 09/2012; 7(9):e46038. DOI:10.1371/journal.pone.0046038 · 3.23 Impact Factor
Available from: James A Deane
- "Increased proliferation of epithelial cells is a driver of cyst formation and a distinctive feature of PKD that is exemplified by the pathogenesis of the most common form of the disease, autosomal dominant PKD (ADPKD) [2,3]. In ADPKD, cysts have been reported to originate from the clonal expansion of epithelial cells with an inherited mutation plus an acquired somatic mutation of one of two ADPKD genes (PKD1 or PKD2)[4-7]. Autosomal recessive PKD (ARPKD) is a rarer childhood onset form of the disease whose pathogenesis also involves high levels of epithelial proliferation . "
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Polycystic Kidney Disease (PKD) is a genetic condition in which dedifferentiated and highly proliferative epithelial cells form renal cysts and is frequently treated by renal transplantation. Studies have reported that bone marrow-derived cells give rise to renal epithelial cells, particularly following renal injury as often occurs during transplantation. This raises the possibility that bone marrow-derived cells from a PKD-afflicted recipient could populate a transplanted kidney and express a disease phenotype. However, for reasons that are not clear the reoccurrence of PKD has not been reported in a genetically normal renal graft. We used a mouse model to examine whether PKD mutant bone marrow-derived cells are capable of expressing a disease phenotype in the kidney.
Wild type female mice were transplanted with bone marrow from male mice homozygous for a PKD-causing mutation and subjected to renal injury. Y chromosome positive, bone marrow-derived cells in the kidney were assessed for epithelial markers.
Mutant bone marrow-derived cells were present in the kidney. Some mutant cells were within the bounds of the tubule or duct, but none demonstrated convincing evidence of an epithelial phenotype.
Bone marrow-derived cells appear incapable of giving rise to genuine epithelial cells and this is the most likely reason cysts do not reoccur in kidneys transplanted into PKD patients.
BMC Nephrology 08/2012; 13(1):91. DOI:10.1186/1471-2369-13-91 · 1.69 Impact Factor
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