TY - JOUR
T1 - LRP5 variants may contribute to ADPKD
AU - Cnossen, Wybrich R.
AU - Morsche, Rene H. M. te
AU - Hoischen, Alexander
AU - Gilissen, Christian
AU - Venselaar, Hanka
AU - Mehdi, Soufi
AU - Bergmann, Carsten
AU - Losekoot, Monique
AU - Breuning, Martijn H.
AU - Peters, Dorien J. M.
AU - Veltman, Joris A.
AU - Drenth, Joost P. H.
PY - 2016/2
Y1 - 2016/2
N2 - 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.
AB - 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.
U2 - 10.1038/ejhg.2015.86
DO - 10.1038/ejhg.2015.86
M3 - Article
C2 - 25920554
SN - 1018-4813
VL - 24
SP - 237
EP - 242
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 2
ER -