Autosomal Dominant Polycystic Kidney: Molecular Genetics

Molecular Genetics: Autosomal dominant polycystic kidney disease (ADPKD) is inherited as an autosomal dominant disorder with complete penetrance (by age 80 years). It is caused by a wide range of mutations in two genes, PKD1 on chromosome 16p13.3 (85%-90% of cases) or PKD2 on chromosome 4q21 (10%-15% of cases). A small subset of patients don’t carry either mutation, suggesting the possibility of a third locus (PKD3). About 25% of patients have no family history and represent new mutations. Although the inheritance pattern is autosomal dominant, both alleles of the involved genes have to lose function for the disease to develop. Thus individuals with ADPKD inherit one defective copy of the involved gene and acquire mutation in the other allele in the somatic cells of the kidney.

PKD1 encodes polycystin-1 – a transmembrane glycoprotein receptor involved in cell signaling in renal tubular epithelial cells, especially in the distal nephron. PKD2 encodes polycystin-2 which is expressed throughout the renal tubules and in many extrarenal tissues. It functions as a sodium/calcium ion channel and regulates intracellular calcium levels. Phenotypically, PKD1- and PKD2-mutated cases are similar; however, PKD2 mutations produce milder disease with older age at diagnosis and delayed onset of hypertension and renal failure. The pathophysiology of polycystin mutations is discussed in the next image. Image credit: Ferreira et al. Polycystic Kidney Disease. Chapter 7 - Polycystins and Molecular Basis of Autosomal Dominant Polycystic Kidney Disease, p 139-167; Codon Publications, Brisbane (AU). Nov. 2015. Used under Creative Commons Attribution 4.0 International License (CC BY 4.0); Codon Publications, Brisbane (AU). Nov. 2015. Used under Creative Commons Attribution 4.0 International License (CC BY 4.0)