SNOMEDCT: 253878003; ORPHA: 2924; DO: 0050770;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.2 | Polycystic liver disease 1 | 174050 | Autosomal dominant | 3 | PRKCSH | 177060 |
A number sign (#) is used with this entry because of evidence that polycystic liver disease-1 with or without kidney cysts (PCLD1) is caused by heterozygous mutation in the PRKCSH gene (177060) on chromosome 19p13.
Polycystic liver disease-1 is an autosomal dominant condition characterized by the presence of multiple liver cysts of biliary epithelial origin. Although the clinical presentation and histologic features of polycystic liver disease in the presence or absence of autosomal dominant polycystic kidney disease (see, e.g., PKD1, 173900) are indistinguishable, PCLD1 is a genetically distinct form of isolated polycystic liver disease (summary by Reynolds et al., 2000). A subset of patients (28-35%) may develop kidney cysts that are usually incidental findings and do not result in clinically significant renal disease (review by Cnossen and Drenth, 2014).
Genetic Heterogeneity of Polycystic Liver Disease
See also PCLD2 (617004), caused by mutation in the SEC63 gene (608648) on chromosome 6q21; PCLD3 (617874), caused by mutation in the ALG8 gene (608103) on chromosome 11p; and PCLD4 (617875), causes by mutation in the LRP5 gene (603506) on chromosome 11q13.
Berrebi et al. (1982) suggested that polycystic liver disease exists as an autosomal dominant entity independent of polycystic kidney disease, which in a considerable but uncertain proportion of cases is associated with hepatic cysts. They described a family in which 2 sisters and the 2 daughters of 1 of the sisters had polycystic liver disease without involvement of the kidneys. One of the 'daughters' had 4 children and 7 grandchildren, all apparently unaffected. The authors suggested that either the 4 'children' did not inherit their mother's PCLD gene or had not yet expressed it because of younger age, none being over age 35 years. In fact, the affected women in the family of Berrebi et al. (1982) did show single cysts or a small number of cysts in the kidney, and at least 1 had 'numerous small 2-3 mm cysts...throughout the pancreas.' The authors pointed to the family reported by Sotaniemi et al. (1979) and Luoma et al. (1980) as another probable example of the distinct entity.
Karhunen and Tenhu (1986) also presented evidence supporting the notion that adult polycystic liver disease is an entity separate from adult polycystic kidney disease. In 22 cases of either polycystic disease of the liver or polycystic disease of the kidney that were found in 33,700 medicolegal autopsies, both organs were affected in only 1 case. In another case of adult PKD, the liver was macroscopically normal but contained microcysts and typical von Meyenburg complexes from which the cysts originate. Cerebral hemorrhage was found only with adult PKD and was not observed in cases of only PCLD. The authors planned to study the families of their probands with PCLD.
Cornec-Le Gall et al. (2018) reported a 49-year-old man with PCLD1 with renal cysts. He had predominant polycystic liver disease requiring liver resection, and 8 cysts in the left kidney. A right nephrectomy was performed for atrophic cystic kidney with suspected malignancy.
The transmission pattern of PCLD1 in the families reported by Drenth et al. (2003) was consistent with autosomal dominant inheritance.
The genetically distinct nature of isolated polycystic liver disease was supported by the finding of Reynolds et al. (2000) that the causative gene in a family with PCLD mapped to 19p13.2-p13.1 by linkage analysis, with a maximum lod score of 10.3. The authors suggested that availability of genetic linkage information should facilitate diagnosis and study of this underdiagnosed disease entity, and that identification of the PCLD gene will be instrumental in understanding the pathogenesis of cyst formation in the liver, both in isolated PCLD and in autosomal dominant PKD.
Drenth et al. (2003) narrowed the linkage assignment of the PCLD1 locus on 19p to a genomic interval containing 78 genes and EST clusters. In the absence of a clear candidate gene, they carried out exon screening using flanking intronic primers. After sequencing 677 exons representing 94% of exons in the genetic region, they detected a heterozygous mutation at a splice acceptor site of the PRKCSH gene (177060.0001) in affected members of 3 families and heterozygosity for a splice donor site mutation (177060.0002) in affected members of a fourth family.
Li et al. (2003) found heterozygous mutations in the PRKCSH gene (see, e.g., 177060.0003-177060.0006) in several families with PCLD, including 2 families studied by Reynolds et al. (2000).
In a 49-year-old man with PCLD1 with kidney cysts, Cornec-Le Gall et al. (2018) identified a heterozygous truncating mutation in the PRKCSH gene (Y462X; 177060.0007). Functional studies of the variant and studies of patient cells were not performed.
Janssen et al. (2011) found somatic loss of the wildtype PRKCSH allele in 54 (76%) of 71 renal cysts collected from 8 patients with heterozygous germline mutations in the PRKCSH gene. The cysts with LOH also showed lack of the PRKCSH-encoded protein hepatocystin. The findings supported the 2-hit hypothesis for disease pathogenesis, suggesting that the disorder is recessive at the cellular level and that loss of PRKSCH is an important step in cystogenesis.
Associations Pending Confirmation
For discussion of a possible association between polycystic liver disease with or without kidney cysts and variation in the SEC61B gene, see 609214.0001 and 609214.0002.
Berrebi, G., Erickson, R. P., Marks, B. W. Autosomal dominant polycystic liver disease: a second family. Clin. Genet. 21: 342-347, 1982. [PubMed: 7116679] [Full Text: https://doi.org/10.1111/j.1399-0004.1982.tb01381.x]
Cnossen, W. R., Drenth, J. P. H. Polycystic liver disease: an overview of pathogenesis, clinical manifestations and management. Orphanet J. Rare Dis. 9: 69, 2014. Note: Electronic Article. [PubMed: 24886261] [Full Text: https://doi.org/10.1186/1750-1172-9-69]
Cornec-Le Gall, E., Torres, V. E., Harris, P. C. Genetic complexity of autosomal dominant polycystic kidney and liver diseases. J. Am. Soc. Nephrol. 29: 13-23, 2018. [PubMed: 29038287] [Full Text: https://doi.org/10.1681/ASN.2017050483]
Drenth, J. P. H., te Morsche, R. H. M., Smink, R., Bonifacino, J. S., Jansen, J. B. M. J. Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nature Genet. 33: 345-348, 2003. [PubMed: 12577059] [Full Text: https://doi.org/10.1038/ng1104]
Janssen, M. J., Waanders, E., Te Morsche, R. H. M., Xing, R., Dijkman, H. B. P. M., Woudenberg, J., Drenth, J. P. H. Secondary, somatic mutations might promote cyst formation in patients with autosomal dominant polycystic liver disease. Gastroenterology 141: 2056-2063, 2011. [PubMed: 21856269] [Full Text: https://doi.org/10.1053/j.gastro.2011.08.004]
Karhunen, P. J., Tenhu, M. Adult polycystic liver and kidney diseases are separate entities. Clin. Genet. 30: 29-37, 1986. [PubMed: 3757294] [Full Text: https://doi.org/10.1111/j.1399-0004.1986.tb00565.x]
Li, A., Davila, S., Furu, L., Qian, Q., Tian, X., Kamath, P. S., King, B. F., Torres, V. E., Somlo, S. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am. J. Hum. Genet. 72: 691-703, 2003. [PubMed: 12529853] [Full Text: https://doi.org/10.1086/368295]
Luoma, P. V., Sotaniemi, E. A., Ehnholm, C. Low high-density lipoprotein and reduced antipyrine metabolism in members of a family with polycystic liver disease. Scand. J. Gastroent. 15: 869-873, 1980. [PubMed: 7209396] [Full Text: https://doi.org/10.3109/00365528009181544]
Reynolds, D. M., Falk, C. T., Li, A., King, B. F., Kamath, P. S., Huston, J., III, Shub, C., Iglesias, D. M., Martin, R. S., Pirson, Y., Torres, V. E., Somlo, S. Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am. J. Hum. Genet. 67: 1598-1604, 2000. [PubMed: 11047756] [Full Text: https://doi.org/10.1086/316904]
Sotaniemi, E. A., Luoma, P. V., Arvensivu, P. M., Sotaniemi, K. A. Impairment of drug metabolism in polycystic non-parasitic kidney disease. Brit. J. Clin. Pharm. 8: 331-335, 1979. [PubMed: 508507] [Full Text: https://doi.org/10.1111/j.1365-2125.1979.tb04714.x]