# Polycystic kidney disease 3 (autosomal dominant)

Polycystic kidney disease 3 (autosomal dominant) is a protein that in humans is encoded by the PKD3 gene.
Polycystic kidney disease (ADPKD) is a life threatening hereditary disorder; it is characterized by the development of fluid-filled cyst formation and expansion of the kidney and other organs. It is an autosomal dominant disease, and it is the most common hereditary disorders with a rate of occurrence of approximately 1 in 1000.

## Characteristics

ADPKD is an autosomal dominant disease, classified into three types, with the chromosomal location of the responsible gene in parentheses: PKD1 (16 Chr), PKD2 (4 Chr), and PKD3 (11 Chr). Mutations in the three different genes PKD1, PKD2, and PKD3 cause a very similar disorder of the autosomal dominant form of ADPKD. The PKD3 gene is located on chromosome number 11q12.3; the phenotype MIM number is 600666.
PKD3 disease is the result of a mutation in the GANAB gene. The GANAB gene encodes the alpha subunit of glucosidase II and a member of the glycosyl hydrolase 31 family of proteins. The heterodimeric enzyme glucosidase II plays a role in protein folding and quality control by cleaving glucose residues from immature glycoproteins in the endoplasmic reticulum. The expression of the protein is elevated in lung tumor tissue. Any mutation in this gene causes autosomal dominant polycystic kidney and liver disease.
PKD3 occurs in adults and sometimes shows symptoms in children. PKD3 is an autosomal dominant inheritance gene that leads to renal cysts. It is related to the liver cysts that sometimes causes organ dysfunction. It is usually detected in middle to late aged individuals who develop severe cysts in kiddy and liver. However, the renal disease is mild and very few patients have hypertension, it does not happen regularly. Unlike liver disease, which develops as a wide spectrum of severity; some individuals have no cysts, while others have severe liver involvement in PKD.

## Clinical features

In an analysis of 20 patients from nine unrelated families who developed PKD with heterozygous mutations in the GANAB gene. Five of the mutations from the GANAB gene were predicted to result in a short protein (frameshift, nonsense, or splicing), and three missense mutations. Seven of the families had a diagnosis of PKD, while the other two families had a diagnosis of polycystic liver disease (PCLD). Most of the patients developed during adulthood , except one patient who showed symptoms at the age of 9 years old. The medical records indicated that the renal disease was insignificant. Also, very few of them had high blood pressure. Renal imaging was also done, which presented variable numbers of multiple cysts (less than 10 to more than 40). Of those suffering from PCLD, some had no cysts while others developed severe disease, requiring surgery. Therefore, this showed that GANAB-related PKD and PCLD are not necessarily separate diseases, but that there was significant phenotypic overlap between the two, and that PKD3 is responsible for this disease.

## Treatment

There is no specific treatment for PKD3. However, a lot of research is going on to mimic the symptoms. Regular monitoring and following up on the complications of this disease can assist in maintaining the health of the individual and extend their life span. Recent research shows that treatment with protein kinase C (PKC) inhibitors prevented the increase in PKD3 activity induced by constitutively active Rac (V12; RacV12) and aluminum fluoride Galpha12/13.

## Mechanism

* Both Galpha12/13 and Rac are important components in the signal transduction pathways that mediate bombesin receptor-induced PKD3 activation.
* The addition of aluminum fluoride to COS-7 cells co-transfected with PKD3 and Galpha13/12 leads to PKD3 activation. This is related to a transient plasma membrane translocation of cytosolic PKD3.
* The catalytic domain of PKD3 can localize to the nucleus when expressed without the kinase domain. Moreover, the catalytic activation of PKD3 in response to RacV12, Galpha12/13 signaling, and bombesin correlated with Ser-731/735 phosphorylation in the activation loop of this enzyme.