PNAS presents paper about the identification of LRP5 mutations in polycystic liver disease

Cnossen, Wybrich

Wybrich Cnossen (photo) and colleagues from the Department of Gastroenterology and Hepatology (supervision Professor Joost P.H. Drenth), and the Department of Human Genetics (supervision Professor Joris A. Veltman) published their research in 'Proceedings of the National Academy of Sciences of the United States of America' (PNAS). The manuscript is entitled 'Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis'. This original research describes the identification of unique LRP5 mutations in polycystic liver disease (PCLD) families by next generation sequencing.  

PCLD is a Mendelian disorder inherited in an autosomal dominant fashion. Patients with a germline mutation in the PRKCSH  gene or SEC63 gene develop multiple hepatic cysts. The genetic cause of hepatic cystogenesis remained unclear in the majority of PCLD patients (~80%). Recently, we identified that germline mutations in anothergene may cause the similar liver phenotype.  

Whole-exome sequencing was performed in an extended PCLD family with a clear autosomal dominant inheritance pattern. No pathogenic variants were present in both PCLD genes and known disease-related genes in affected individuals. Sanger sequencing confirmed that the only private nonsynonymous variant that cosegregated completely with the disease was a mutation located on chromosome 11q13.2 in the  low-density lipoprotein receptor-related protein 5 (LRP5) gene.  

These findings give new insight into the pathofysiology of PCLD. LRP5 is a transmembrane protein and co-receptor of the canonical Wnt signaling. Functional analysis presented that Wnt signal transduction is reduced in mutant LRP5 compared to wild-type LRP5. Therefore, a dysregulated canonical Wnt signaling contributes to development of hepatic cysts.  

Wybrich R. Cnossen1, René H.M. te Morsche1, Alexander Hoischen2, Christian Gilissen2, Melissa Chrispijn1, Hanka Venselaar3, Soufi Mehdi4, Carsten Bergmann5,6, Joris A. Veltman2, Joost P.H. Drenth1

Author Affiliations:
1Department of Gastroenterology and Hepatology, 2Department of Human Genetics, 3Center for Molecular and Biomolecular Informatics, Institute for Genetic & Metabolic Disease (IGMD), Radboud university medical center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, 4Department of Gastrointestinal and Oncological Surgery, Faculty of Medicine, University Mohammed First, Oujda, Marocco, 5Center for Human Genetics, Bioscientia, Ingelheim, Germany, 6Department of Nephrology and Center for Clinical Research, University Hospital Freiburg, Freiburg, Germany

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