| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q13.2 | Polycystic liver disease 4 with or without kidney cysts | 617875 | Autosomal dominant | 3 | LRP5 | 603506 |
A number sign (#) is used with this entry because of evidence that polycystic liver disease-4 with or without kidney cysts (PCLD4) is caused by heterozygous mutation in the LRP5 gene (603506) on chromosome 11q13.
PCLD4 is an autosomal dominant disease characterized by adult-onset of liver cysts arising from the bile duct epithelium. Some patients may develop a few kidney cysts, but these are often incidental and do not result in renal failure (summary by Cnossen et al., 2014).
For a discussion of genetic heterogeneity of polycystic liver disease, see PCLD1 (174050).
Cnossen et al. (2014) reported a large multigenerational Dutch family in which at least 16 individuals spanning 3 generations had polycystic liver disease. The severity of the disease varied within the family. Many patients also had a few kidney cysts, although none had clinically significant renal disease. Another smaller Dutch family, a smaller Moroccan family, and a Dutch patient with sporadic disease were also reported. Clinical details were sparse.
The transmission pattern of PCLD4 in the families reported by Cnossen et al. (2014) was consistent with autosomal dominant inheritance. There was some evidence of age-related incomplete penetrance.
In affected individuals from 4 unrelated families with PCLD4, Cnossen et al. (2014) identified 4 different heterozygous missense mutations in the LRP5 gene (603506.0035-603506.0038). Two mutations affected the extracellular domain, and 2 affected the intracellular domain. The mutation in the first family was found by whole-exome sequencing and confirmed by Sanger sequencing; the 3 other mutations were found by direct sequencing of the LRP5 gene in a cohort of 150 probands with cystic liver disease. The mutations segregated with the disorder in the families. In vitro functional expression studies of 2 of the variants showed that they resulted in decreased WNT (see, e.g., 164820) signaling activation in response to Wnt3a (606359) compared to wildtype, as well as altered expression of some target genes in this pathway. None of the patients carrying mutations had evidence of clinical features of other LRP5-related disorders, including bone density or ocular abnormalities.
Associations Pending Confirmation
Based on the putative overlap between polycystic liver disease and polycystic kidney disease (PKD), Cnossen et al. (2016) screened the LRP5 gene in 79 probands with PKD. Four different missense variants (W560C, R1036Q, R1135C, and Q1156H) were identified in 4 probands. However, in 2 families (families A and D), there was not clean segregation of the LRP5 variant with the disorder, and individuals also carried variants in the PKD1 gene (601313). The R1036Q variant identified in a patient with sporadic disease (family B) had a high frequency (1/245) in public databases. The R1135C variant in family C also had a relatively high frequency (1/1,300) among European Americans in the Exome Sequencing Project database and was found in the proband's unaffected mother and older sister. In vitro functional expression assays using a luciferase marker demonstrated that 3 of the variants (W560C, R1036Q, and Q1156H) resulted in impaired activation of Wnt3a-induced canonical WNT signaling compared to wildtype. Two variants (W560C and R1036Q) resulted in an increase in AXIN2 (604025) expression. The findings suggested that LRP5 variants may also contribute to kidney cysts by altering Wnt signaling.
Cnossen, W. R., te Morsche, R. H. M., Hoischen, A., Gilissen, C., Chrispijn, M., Venselaar, H., Mehdi, S., Bergmann, C., Veltman, J. A., Drenth, J. P. H. Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis. Proc. Nat. Acad. Sci. 111: 5343-5348, 2014. [PubMed: 24706814] [Full Text: https://doi.org/10.1073/pnas.1309438111]
Cnossen, W. R., te Morsche, R. H. M., Hoischen, A., Gilissen, C., Venselaar, H., Mehdi, S., Bergmann, C., Losekoot, M., Breuning, M. H., Peters, D. J. M., Veltman, J. A., Drenth, J. P. H. LRP5 variants may contribute to ADPKD. Europ. J. Hum. Genet. 24: 237-242, 2016. [PubMed: 25920554] [Full Text: https://doi.org/10.1038/ejhg.2015.86]