PKD2 and cystic kidney disease: The “two-hit” model has been proposed to explain the genetic mechanism of renal cyst formation caused by PKD2 mutations [61,62]: (1) Both proximal and distal tubular epithelial cells of all nephrons carry both mutant and non-mutant PKD2 alleles, which means the individual has a heterozygous germline mutation, which represents the first hit; (2) injuries or other factors may cause mutations in the non-mutant PKD2 allele, resulting in somatic mutations, which represents the second hit, leading to insufficient PKD2 levels in the cells.