LRP5 variants may contribute to ADPKD

Eur J Hum Genet. 2016 Feb;24(2):237-42. doi: 10.1038/ejhg.2015.86.

Wybrich R Cnossen ¹, René H M te Morsche ¹, Alexander Hoischen ², Christian Gilissen ², Hanka Venselaar ³, Soufi Mehdi ⁴, Carsten Bergmann ⁵ ⁶, Monique Losekoot ⁷, Martijn H Breuning ⁷, Dorien J M Peters ⁸, Joris A Veltman ² ⁹, Joost P H Drenth ¹

Affiliations

1 Department of Gastroenterology and Hepatology, Institute for Genetic & Metabolic Disease (IGMD), Radboud Institute for Molecular LifeSciences (RIMLS), Radboud university medical center, Nijmegen, The Netherlands.
2 Department of Human Genetics, Institute for Genetic & Metabolic Disease (IGMD), Radboud Institute for Molecular LifeSciences (RIMLS), Radboud university medical center, Nijmegen, The Netherlands.
3 Center for Molecular and Biomolecular Informatics, Institute for Genetic & Metabolic Disease (IGMD), Radboud Institute for Molecular LifeSciences (RIMLS), Radboud university medical center, Nijmegen, The Netherlands.
4 Department of Gastrointestinal and Oncological Surgery, Faculty of Medicine, University Mohammed First, Oujda, Morocco.
5 Center for Human Genetics, Bioscientia, Ingelheim, Germany.
6 Department of Nephrology and Center for Clinical Research, University Hospital Freiburg, Freiburg, Germany.
7 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
8 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
9 Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.

PMID: 25920554 DOI: 10.1038/ejhg.2015.86

Abstract

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.1680G>T; 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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