ArticleProceedings of the National Academy of Sciences of the United States of America2014
Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed, 88 citations in OpenAlex.
- Pansomatostatin Agonist Pasireotide Long-Acting Release for Patients with Autosomal Dominant Polycystic Kidney or Liver Disease with Severe Liver Involvement: A Randomized Clinical Trial.Clinical journal of the American Society of Nephrology : CJASN · 2020Trial
- Genetic contributors to osteoporosis in pregnancy and lactation associated osteoporosis (PLO).Bone · 2026Article
- An NGS-based investigation of copy number variants in the diagnosis and severity of adult polycystic kidney disease.European journal of human genetics : EJHG · 2026Article
- The spectrum of diseases, genetic landscape and new mutation sites of hereditary cystic kidney disease.Clinical kidney journal · 2025Article
- Bilateral Polycystic Kidney Disease and Inferior Vena Cava (IVC) Thrombosis: A Cadaveric Study.Cureus · 2025Article
- Clinical manifestation, epidemiology, genetic basis, potential molecular targets, and current treatment of polycystic liver disease.Orphanet journal of rare diseases · 2024Review
- A familial missense variant in the Alzheimer's disease gene SORL1 impairs its maturation and endosomal sorting.Acta neuropathologica · 2024Article
- A familial missense variant in the Alzheimer's Disease genebioRxiv : the preprint server for biology · 2023Article
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- NOTCH signalling - a core regulator of bile duct disease?Disease models & mechanisms · 2023Review
- Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.Genes · 2023Article
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- Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.JHEP reports : innovation in hepatology · 2022Article
- Genetics, pathobiology and therapeutic opportunities of polycystic liver disease.Nature reviews. Gastroenterology & hepatology · 2022Review
- GANAB andInternational journal of molecular sciences · 2022Review
- LRP5 promotes cancer stem cell traits and chemoresistance in colorectal cancer.Journal of cellular and molecular medicine · 2022Article
- Polycystic Liver Disease: Advances in Understanding and Treatment.Annual review of pathology · 2022Review
- Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment.Hepatic medicine : evidence and research · 2022Review
- Molecular Mechanisms of Isolated Polycystic Liver Diseases.Frontiers in genetics · 2022Review
- Association of a novelAnnals of translational medicine · 2021Article
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Authors and funding
10 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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