The Genetic and Cellular Basis of Autosomal Dominant Polycystic Kidney Disease-A Primer for Clinicians

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders worldwide. In recent decades, the field has undergone a revolution, starting with the identification of causal ADPKD genes, including PKD1, PKD2, and the recently identified GANAB. In addition, advances defining the genetic mechanisms, protein localization and function, and the identification of numerous pathways involved in the disease process, have contributed to a better understanding of this illness. Together, this has led to a better prognosis, diagnosis, and treatment in clinical practice. In this mini review, we summarize and discuss new insights about the molecular mechanisms underlying ADPKD, including its genetics, protein function, and cellular pathways.

Keywords: autosomal dominant polycystic kidney disease; diagnosis; genetics; molecular biology; therapy.

Figure 1

Chromosome localization and genomic structure of PKD1, PKD2, and GANAβ genes and structure of polycystin-1 (PC1) and polycystin-2 (PC2). (A) Schematic representation of chromosomes and genomic structure for the genes. (B) Representation of PKD1 and PKD2 protein products: PC1 and PC2. *GIIα (encoded by GANAβ) is not included because the tertiary structure of the protein is not available in the bibliography or protein date bases.

Figure 2

Diagram of the localization of the polycystic kidney disease (PKD) proteins, the pathways implicated in its pathogenesis, and putative therapeutic targets. The polycystin-1 (PC1) and polycystin-2 (PC2), associated with autosomal dominant polycystic kidney disease (ADPKD), and FPC and DIZP1L, associated with autosomal recessive polycystic kidney disease (ARPKD), are ciliary proteins and have functions in relation with the primary cilia. GANAβ [associated with ADPKD and autosomal dominant polycystic liver disease (ADPLD)], together with the classical genes of the ADPLD, PRKCSH, and Sec63, is localized in the endoplasmic reticulum (ER) and plays a role in the translocation and folding of the protein maturation. PC1 and PC2 form a receptor–channel complex in the cilium and is implicated in the Ca²⁺ pathway. PC2 also regulates intracellular calcium in the ER. PC mutations result in deregulation of Ca²⁺ leading an increase in cAMP and upregulation of the PKA and MAPK pathways. Abbreviations: RyR, ryanodine receptor; IP3R, IP3 receptor; PDE, phosphodiesterase; AC-VI, adenylyl cyclase 6; Gs and Gi, guanosine nucleotide-binding proteins; V2R, V2 receptor; cAMP, cyclic AMP; PKA, protein kinase A; MAPK, MAP kinases; SIRT1, sirtuin 1.