Polycystic Liver Disease 2 With Or Without Kidney Cysts

A number sign (#) is used with this entry because of evidence that polycystic liver disease-2 with or without kidney cysts (PCLD2) is caused by heterozygous mutation in the SEC63 gene (608648) on chromosome 6q21.

Description

PCLD2 is an autosomal dominant disease characterized by the presence of multiple liver cysts resulting from structural changes in the biliary tree during development. Abnormal biliary structures may be present early in life, but they usually remain asymptomatic until cyst growth initiates during adulthood. In advanced stages, patients may develop massively enlarged livers, which cause a spectrum of clinical features and complications. Genetic studies suggest that an accumulation of somatic hits in cyst epithelium determines the rate of cyst formation. 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).

For a discussion of genetic heterogeneity of polycystic liver disease, see PCLD1 (174050).

Clinical Features

Pirson et al. (1996) reported a 3-generation family with adult polycystic liver disease. The proband was a 61-year-old man with highly symptomatic PCLD, who was diagnosed at age 50. The patient's mother also had massive PCLD without known kidney disease; she died of cancer of unknown origin at age 80. The proband's sister had extensive PCLD with mild hepatomegaly and without kidney cysts. The proband's daughter had marked PCLD with normal liver size, but the proband's son had no liver cysts. Information added in proof seemed to establish the autosomal dominant inheritance of the disorder: a 56-year-old maternal first cousin of the proband was found to have extensive PCLD with mild hepatomegaly without cysts in the kidneys, pancreas, or spleen. He presumably inherited the disorder from his father, the maternal uncle of the proband. Kidney cysts were not reported in this family.

Davila et al. (2004) reported 8 unrelated families in which several members had liver cysts. Several of the families had previously been reported, including the family reported by Pirson et al. (1996). Detailed clinical information was not provided in the report of Davila et al. (2004).

Inheritance

The transmission pattern of PCLD2 in the families reported by Davila et al. (2004) was consistent with autosomal dominant inheritance.

Mapping

Davila et al. (2004) performed genomewide linkage analysis on 10 individuals with autosomal dominant PCLD from multiply affected families in whom mutations in the PRKCSH gene (177060) were excluded. They found linkage to chromosome 6q21-q23.

Molecular Genetics

In affected members of 8 families with autosomal PCLD2 without kidney cysts, Davila et al. (2004) identified 7 heterozygous mutations in the SEC63 gene (see, e.g., 608648.0001-608648.0004). A nonsense mutation (W58X; 608648.0001) occurred in 2 probands from the central U.S. who were not known to be related. Three probands from Finland had different mutations (608648.0002, 608648.0003, and 608648.0004). The mutations were found by linkage analysis followed by candidate gene sequencing. Functional studies of the variant and studies of patient cells were not performed. Although cysts occurred only in the liver, SEC63 was expressed in all tissues tested. The final count indicated mutations in SEC63 in 8 of 66 probands (approximately 12%) in their sample that included both familial cases and individual probands not known to have a positive family history. Mutations in PRKCSH and SEC63 together account for less than one-third of autosomal dominant PCLD cases, indicating that there is at least 1 more locus associated with this disease. The SEC63 gene encodes a component of the protein translocation machinery in the endoplasmic reticulum; the PRKCSH gene encodes the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum. Thus, these findings together suggest a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial endoplasmic reticulum proteins in human polycystic disease.