A number sign (#) is used with this entry because of evidence that polycystic kidney disease-3 with or without polycystic liver disease (PKD3) is caused by heterozygous mutation in the GANAB gene (104160) on chromosome 11q13.

Polycystic kidney disease-3, a form of autosomal dominant PKD (ADPKD), is characterized by renal cysts, often associated with liver cysts, that may lead to organ dysfunction. Affected individuals usually present in mid to late adulthood with progressive cysts in the kidney and/or liver. The renal disease is relatively mild, and only some patients develop hypertension; renal insufficiency usually does not occur. The liver disease shows a wide spectrum of severity: some patients have no cysts, whereas others have severe liver involvement (summary by Porath et al., 2016).

For a discussion of genetic heterogeneity of PKD, see PKD1 (173900).

Porath et al. (2016) reported 20 patients from 9 unrelated families with autosomal dominant polycystic kidney and/or liver disease associated with heterozygous mutations in the GANAB gene. Seven of the families presented with a primary diagnosis of PKD, and 2 with a primary diagnosis of polycystic liver disease (PCLD), although there was significant phenotypic overlap between the 2 groups. Most patients presented in mid- to late-adulthood, although 1 boy became symptomatic at age 9 years. Overall, the renal disease was relatively mild without renal insufficiency, and less than half of patients had high blood pressure. Renal imaging showed variable numbers of multiple cysts (from less than 10 to more than 40) in all patients, including those with a primary diagnosis of PCLD. The liver disease was variable and ranged from no cysts to severe disease requiring surgical intervention in 2 unrelated patients in their forties. Liver imaging showed cysts in most patients with a primary diagnosis of PKD, and in all 5 patients with a primary diagnosis of PCLD. A father and daughter (family M263 with PKD) had mild kidney and significant liver cystic disease, but no high blood pressure. Two sisters (family M641) had mild PKD, but only 1 had multiple liver cysts. However, both had intracranial aneurysms, and the deceased father reportedly had a ruptured aneurysm. In another family (family 290100), a father and son had mild PKD, but only the father had multiple liver cysts. Porath et al. (2016) concluded that GANAB-related PKD and PCLD are not necessarily separate diseases, but rather share overlapping features whose variability may be determined by additional genetic factors.

Clinical Variability

Besse et al. (2018) reported a large family (family T90) in which 6 individuals spanning 2 generations had isolated polycystic liver disease associated with a heterozygous mutation in the GANAB gene (104160.0007). Clinical details of the family were not provided, but they apparently did not have kidney cysts.

The transmission pattern of PKD3 in family M263 reported by Porath et al. (2016) was consistent with autosomal dominant inheritance.

In 20 affected members of 9 unrelated families with PKD3, Porath et al. (2016) identified 8 different heterozygous mutations in the GANAB gene (see, e.g., 104160.0001-104160.0006). Five of the mutations were predicted to result in a truncated protein (frameshift, nonsense, or splicing), and 3 were missense mutations. The mutation in the first family was found by whole-exome sequencing of 6 families with ADPKD; subsequent mutations were identified by Sanger sequencing of the GANAB gene in 321 families with ADPKD and/or ADPLD. Complete knockdown of GANAB in human renal cells resulted in absence of the mature N-terminal polycystin-1 (PKD1; 601313), but full-length polycystin-1 and polycystin-2 (PKD2; 173910) were present, indicating that GANAB plays a major role in the maturation of these proteins. Heterozygous-null GANAB renal cells had a 50% depletion of mature N-terminal polycystin-1. Transfection of the 3 missense mutations into GANAB-null renal cells failed to rescue the lack of surface PKD1 expression, indicating that these mutations resulted in a loss of enzyme function. The authors noted that PRKCSH (177060), mutations in which cause polycystic liver disease-1 (PCLD1; 174050) without renal cysts, and GANAB are subunits of the same protein, so it is not clear why GANAB mutations result in more renal disease. The highly variable phenotype was typical of polycystic kidney and liver disease, and allelic effects did not appear to explain this variability. The cystogenesis was most likely driven by defects in maturation of PKD1, mutations in which cause autosomal dominant polycystic kidney disease-1 (173900).