Whole-exome sequencing reveals
            <i>LRP5</i>
            mutations and canonical Wnt signaling associated with hepatic cystogenesis

Cnossen, Wybrich R; Morsche, R.H.M. te; Hoischen, Alexander; Gilissen, Christian; Chrispijn, Melissa; Venselaar, Hanka; Soufi, Mehdi; Bergmann, Carsten; Veltman, Joris A.; Drenth, Joost P.H.

doi:10.1073/pnas.1309438111

Cited by 82 publications

(67 citation statements)

References 46 publications

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“…23,24 Our findings are in line with the hypothesis that genes encoding Wnt/β-catenin signaling partners may be candidate loci for cystic disorders. 13,20 We postulate that LRP5 variants may render ADPKD patients more susceptible to the development of polycystic liver although further studies are needed to validate our findings.…”

Section: Lrp5 Variants In Adpkd Wr Cnossen Et Almentioning

confidence: 68%

“…Luciferase activity assays of four LRP5 constructs decrease Wnt3a-induced signal activation across various cell lines (Figure 2). 13 In addition, the expression of AXIN2, a Wnt signaling gene is enhanced in the presence of three LRP5 mutants (Supplementary Figure S5). This suggests that there is constitutive activation of the Wnt signaling as a result of these LRP5 variants.…”

Section: Discussionmentioning

confidence: 99%

“…The association of LRP5 variants with hepatic cystogenesis was identified in an extended PCLD pedigree. 13 The fact that polycystic livers are present in up to 94% of ADPKD patients 2 prompted us to investigate the possible pathogenic role of LRP5 variants in ADPKD patients.…”

Section: Discussionmentioning

confidence: 99%

“…13 As PCLD is the most common extra-renal feature in ADPKD patients, we hypothesized that LRP5 variants may contribute to hepatic and renal disease heterogeneity in ADPKD. We addressed the role of LRP5 by screening all 23 exons in 79 unlinked and/or sporadic ADPKD patients, and performed some functional analyses.…”

Section: Introductionmentioning

confidence: 99%

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LRP5 variants may contribute to ADPKD

et al. 2015

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Mutations in Polycystic Kidney Disease proteins (PKD1 or PKD2) are causative for autosomal dominant polycystic kidney disease (ADPKD). However, a small subset of ADPKD probands do not harbor a mutation in any of the known genes. Low density lipoprotein Receptor-related Protein 5 (LRP5) was recently associated with hepatic cystogenesis in isolated polycystic liver disease (PCLD). Here, we demonstrate that this gene may also have a role in unlinked and sporadic ADPKD patients. In a cohort of 79 unrelated patients with adult-onset ADPKD, we identified a total of four different LRP5 variants that were predicted to be pathogenic by in silico tools. One ADPKD patient has a positive family history for ADPKD and variant LRP5 c.1680G4T; p.(Trp560Cys) segregated with the disease. Although also two PKD1 variants probably affecting protein function were identified, luciferase activity assays presented for three LRP5 variants significant decreased signal activation of canonical Wnt signaling. This study contributes to the genetic spectrum of ADPKD. Introduction of the canonical Wnt signaling pathway provides new avenues for the study of the pathophysiology.

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Section: Lrp5 Variants In Adpkd Wr Cnossen Et Almentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LRP5 variants may contribute to ADPKD

et al. 2015

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“…29 In support of this, a recent study revealed that LRP5 mutations and canonical Wnt signaling are associated with hepatic cystogenesis. 30 However, Wnt/ b-catenin signaling is not involved in renal cystic formation of the mutant mice of Invs that encodes a cilial protein inversin or nephrocystin-2. 31 b-catenin/TCF signaling activity is also not ectopically activated in PKD1 and PKD2 mutants, two different models of polycystic kidney, or renal cystic ciliopathy.…”

Section: Lrp6-mediated Wnt/b-catenin Signaling In Renal Development Amentioning

confidence: 99%

LDL Receptor–Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia

Wang

Stokes

Duan

et al. 2016

Journal of the American Society of Nephrology

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Hypoplastic and/or cystic kidneys have been found in both LDL receptor-related protein 6 (Lrp6)-and b-catenin-mutant mouse embryos, and these proteins are key molecules for Wnt signaling. However, the underlying mechanisms of Lrp6/b-catenin signaling in renal development and cystic formation remain poorly understood. In this study, we found evidence that diminished cell proliferation and increased apoptosis occur before cystic dysplasia in the renal primordia of Lrp6-deficient mouse embryos. The expression of Ret protooncogene (Ret), a critical receptor for the growth factor glial cell line-derived neurotrophic factor (GDNF), which is required for early nephrogenesis, was dramatically diminished in the mutant renal primordia. The activities of other representative nephrogenic genes, including Lim1, Pax2, Pax8, GDNF, and Wnt11, were subsequently diminished in the mutant renal primordia. Molecular biology experiments demonstrated that Ret is a novel transcriptional target of Wnt/b-catenin signaling. Wnt agonist lithium promoted Ret expression in vitro and in vivo. Furthermore, Lrp6-knockdown or lithium treatment in vitro led to downregulation or upregulation, respectively, of the phosphorylated mitogen-activated protein kinases 1 and 3, which act downstream of GDNF/ Ret signaling. Mice with single and double mutations of Lrp6 and Ret were perinatal lethal and demonstrated gene dosage-dependent effects on the severity of renal hypoplasia during embryogenesis. Taken together, these results suggest that Lrp6-mediated Wnt/b-catenin signaling modulates or interacts with a signaling network consisting of Ret cascades and related nephrogenic factors for renal development, and the disruption of these genes or signaling activities may cause a spectrum of hypoplastic and cystic kidney disorders.

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Polycystic Liver Diseases

Masyuk

LaRusso

2020

The Liver

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Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis

Cited by 82 publications

References 46 publications

LRP5 variants may contribute to ADPKD

LRP5 variants may contribute to ADPKD

LDL Receptor–Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia

Polycystic Liver Diseases

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