Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway

García-González, Miguel A.; Menezes, Luís F.; Piontek, Klaus; Kaimori, Jun-Ya; Huso, David L.; Watnick, Terry; Onuchic, Luiz Fernando; Guay‐Woodford, Lisa M.; Germino, Gregory G.

doi:10.1093/hmg/ddm141

Cited by 112 publications

(121 citation statements)

References 42 publications

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“…During submission of our article, another group reported that there are genetic interactions between Pkhd1 and Pkd1. 41 Because the gene product of PKD1, PC1, was reported to interact with PC2 and regulate Pkd2-channel activity, 9 -11 our findings combined with theirs draw the conclusion that ADPKD and ARPKD may reside in the same pathogenic pathway.…”

Section: Discussionmentioning

confidence: 61%

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

125

103

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Autosomal recessive polycystic kidney disease is caused by mutations in PKHD1, which encodes the membrane-associated receptor-like protein fibrocystin/polyductin (FPC). FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway. For investigation of this, a mouse model with a gene-targeted mutation in Pkhd1 that recapitulates phenotypic characteristics of human autosomal recessive polycystic kidney disease was produced. The absence of FPC is associated with aberrant ciliogenesis in the kidneys of Pkhd1-deficient mice. It was found that the COOH-terminus of FPC and the NH2-terminus of PC2 interact and that lack of FPC reduced PC2 expression but not vice versa, suggesting that PC2 may function immediately downstream of FPC in vivo. PC2-channel activities were dysregulated in cultured renal epithelial cells derived from Pkhd1 mutant mice, further supporting that both cystoproteins function in a common pathway. In addition, mice with mutations in both Pkhd1 and Pkd2 had a more severe renal cystic phenotype than mice with single mutations, suggesting that FPC acts as a genetic modifier for disease severity in autosomal dominant polycystic kidney disease that results from Pkd2 mutations. It is concluded that a functional and molecular interaction exists between FPC and PC2 in vivo.

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Section: Discussionmentioning

confidence: 61%

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Kim

Fu²,

Hui

et al. 2008

Journal of the American Society of Nephrology

125

103

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“…Direct evidence for genetic interactions between ADPKD and ARPKD loci came from two other mouse studies in which Pkhd1/Pkd1 and Pkhd1/Pkd2 transmutants showed a much more severe renal cystic phenotype than mice bearing a mutation in only one of these genes. 11,14 The high recurrence risk for early and severe polycystic kidney disease in affected pedigrees suggests a common familial modifying background. 15 Here we present the data of eight pedigrees in which the severely affected patients are the only family members that carry other PKD alleles in trans and/or de novo in addition to the familial germ-line mutation (see Figures 1 through 8).…”

mentioning

confidence: 99%

Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney Disease

Bergmann

Bothmer

Brüchle

et al. 2011

Journal of the American Society of Nephrology

211

158

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Autosomal dominant polycystic kidney disease (ADPKD) is typically a late-onset disease caused by mutations in PKD1 or PKD2, but about 2% of patients with ADPKD show an early and severe phenotype that can be clinically indistinguishable from autosomal recessive polycystic kidney disease (ARPKD). The high recurrence risk in pedigrees with early and severe PKD strongly suggests a common familial modifying background, but the mechanisms underlying the extensive phenotypic variability observed among affected family members remain unknown. Here, we describe severely affected patients with PKD who carry, in addition to their expected familial germ-line defect, additional mutations in PKD genes, including HNF-1␤, which likely aggravate the phenotype. Our findings are consistent with a common pathogenesis and dosage theory for PKD and may propose a general concept for the modification of disease expression in other so-called monogenic disorders.

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“…24 More recently renal phenotypes have been described in two mouse models harboring hypomorphic mutations in Pkhd1. 25,26 The Pkhd1 del2/del2 mouse develops renal cysts in the S3 segment of the proximal tubule but not in the collecting duct system. 25 On the other hand, the Pkhd1 del3Ϫ4/del3-4 model develops cysts in the collecting duct and thick ascending limbs of Henle's loop.…”

mentioning

confidence: 99%

“…25 On the other hand, the Pkhd1 del3Ϫ4/del3-4 model develops cysts in the collecting duct and thick ascending limbs of Henle's loop. 26 In the current study, we sought to investigate the role of fibrocystin in human disease by targeting the 5Ј region of the murine Pkhd1. Partial deletion of exon 4 resulted in a hypomorphic allele with persistent protein expression because of cryptic splice site activation and exon skipping.…”

mentioning

confidence: 99%

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Gallagher

Esquivel

Briere

et al. 2008

The American Journal of Pathology

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Autosomal recessive polycystic kidney disease is a hereditary fibrocystic disease that involves the kidneys and the biliary tract. Mutations in the PKHD1 gene are responsible for typical forms of autosomal recessive polycystic kidney disease. We have generated a mouse model with targeted mutation of Pkhd1 by disrupting exon 4, resulting in a mutant transcript with deletion of 66 codons and expression at ϳ30% of wild-type levels. Pkhd1 del4/del4 mice develop intrahepatic bile duct proliferation with progressive cyst formation and associated periportal fibrosis. In addition, these mice exhibit extrahepatic manifestations, including pancreatic cysts, splenomegaly, and common bile duct dilation. The kidneys are unaffected both histologically and functionally. Fibrocystin is expressed in the apical membranes and cilia of bile ducts and distal nephron segments but is absent from the proximal tubule. This pattern is unchanged in orthologous models of autosomal dominant polycystic kidney disease due to mutation in Pkd1 or Pkd2. Mutant fibrocystin in Pkhd1 del4/del4 mice also retains this expression pattern. The hypomorphic Pkhd1 del4/del4 mouse model provides evidence that reduced functional levels of fibrocystin are sufficient for cystogenesis and fibrosis in the liver and pancreas, but not the kidney, and supports the hypothesis of species-dependent differences in susceptibility of tissues to Pkhd1 mutations. (Am J

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Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway

Cited by 112 publications

References 42 publications

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney Disease

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

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