Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.
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.
Departments of Gastroenterology and Hepatology and Human Genetics and Center for Molecular and Biomolecular Informatics, Institute for Genetic and Metabolic Disease, Radboud university medical center, 6500 HB Nijmegen, The Netherlands.
Wybrich R
WR
Cnossen
René H M
RH
te Morsche
Alexander
A
Hoischen
Christian
C
Gilissen
Melissa
M
Chrispijn
Hanka
H
Venselaar
Soufi
S
Mehdi
Carsten
C
Bergmann
Joris A
JA
Veltman
Joost P H
JP
Drenth
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003560:Cysts / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051153:Wnt Proteins
gene identification; β-catenin pathway