Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis
Open accessAbstract
Polycystic livers are seen in the rare inherited disorder isolated polycystic liver disease (PCLD) and are recognized as the most common extrarenal manifestation in autosomal dominant polycystic kidney disease. Hepatic cystogenesis is characterized by progressive proliferation of cholangiocytes, ultimately causing hepatomegaly. Genetically, polycystic liver disease is a heterogeneous disorder with incomplete penetrance and caused by mutations in PRKCSH, SEC63, PKD1, or PKD2. Genome-wide SNP typing and Sanger sequencing revealed no pathogenic variants in hitherto genes in an extended PCLD family. We performed whole-exome sequencing of DNA samples from two members. A heterozygous variant c.3562C > T located at a highly conserved amino acid position (p.R1188W) in the low density lipoprotein receptor-related protein 5 (LRP5) gene segregated with the disease (logarithm of odds score, 4.62) but was not observed in more than 1,000 unaffected individuals. Screening of LRP5 in a PCLD cohort identified three additional mutations in three unrelated families with polycystic livers (p.V454M, p.R1529S, and p.D1551N), again all undetected in controls. All variants were predicted to be damaging with profound structural effects on LRP5 protein domains. Liver cyst tissue and normal hepatic tissue samples from patients and controls showed abundant LRP5 expression by immunohistochemistry. Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation. In conclusion, we demonstrate that germ-line LRP5 missense mutations are associated with hepatic cystogenesis. The findings presented in this study link the pathophysiology of PCLD to deregulation of the canonical wingless signaling pathway.
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All genes involved in ADPLD encode proteins involved in ER trafficking and quality control of glycoproteins, with the exception of LRP5.
“In particular, all genes involved in ADPLD encode proteins involved in the ER trafficking and quality control of glycoproteins. The only exception is the LRP5, a transmembrane protein, part of the LRP5/LRP6/Frizzled co-receptor complex in the canonical Wnt signaling pathway [425].”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [425]
The introductory passage identifies PRKCSH and SEC63 as PCLD genes whose products are in the endoplasmic reticulum and process and fold glycosylated proteins; the Discussion describes LRP5 as a transmembrane Wnt coreceptor. The paper does not establish that *all* other ADPLD genes have this role: it says many PCLD cases may involve genes not yet identified. It also does not specifically describe PRKCSH and SEC63 as involved in ER trafficking. (LLM, conf=0.84)
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Research works printed but not linked: 1
- Waanders E, te Morsche RH, de Man RA, Jansen JB, Drenth JP (2006) Extensive mu- tational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease. Hum Mutat 27(8):830.
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“The only exception is the LRP5, a transmembrane protein, part of the LRP5/LRP6/Frizzled co-receptor complex in the canonical Wnt signaling pathway [425].”
Background
- Authors
- Cnossen, W. R., te Morsche, R. H. M., Hoischen, A., Gilissen, C., Chrispijn, M., Venselaar, H., Mehdi, S., Bergmann, C., Veltman, J. A., & Drenth, J. P. H.
- Affiliations
- Departments of aGastroenterology and Hepatology and
- Human Genetics and
- Radboud University Medical Center (NL)
- Mohamed I University (MA)
- University Medical Center Freiburg (DE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-03-24
- Volume
- 111
- Issue
- 14
- Pages
- 5343-5348
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3986119
- OpenAlex
- W2003194693
- Cited by
- 90
- References
- 49
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 8 · 2021: 9 · 2020: 11 · 2019: 6 · 2018: 7 · 2017: 16 · 2016: 5 · 2015: 8 · 2014: 2
- FWCI
- 6.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Radboud Universiteit
- Radboud Universitair Medisch Centrum
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Keywords
- Wnt/β-catenin signaling, Wingless signaling, cholangiocyte proliferation, autosomal dominant polycystic kidney disease, missense mutations, germline mutations, genetic heterogeneity
- MeSH terms
- Adult, Aged, Cysts, Female, Humans, Liver Diseases, Male, Middle Aged, Mutation, Pedigree, Cohort Studies, Signal Transduction, Polymorphism, Single Nucleotide, Wnt Proteins, Exome, Low Density Lipoprotein Receptor-Related Protein-5
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