What are the genetic features of ADPKD?
ADPKD is a genetically heterogeneous disease, for which two different genes have been identified. PKD1 , located on the short arm of chromosome 16, is responsible for approximately 85% of the cases in which a mutation has been identified, whereas PKD2, located on chromosome 4, accounts for nearly 15% of remaining cases with an identified mutation. PKD1 and PKD2 encode for polycystin-1 and polycystin-2, respectively. These membrane-bound glycoproteins are located in the plasma membrane of the primary cilia and regulate calcium homeostasis. PKD1 is associated with more severe disease compared with PDK2. This is due to the fact that patients with PKD1 develop more cysts at an early age rather than faster cyst growth. There have been hundreds of different pathogenic mutations identified in PKD1 and PKD2 . It is thought that kidney cysts may develop from loss of functional polycystin with somatic inactivation of the normal allele consistent with a “two-hit” mechanism, but other genetic mechanisms may play a role. Between 7% and 10% of ADPKD cases remain genetically unresolved after genetic screening. Data suggest that mutations in GANAB , a coding gene that encodes for a glucosidase-II alpha subunit, may account for approximately 3% of the genetically unresolved ADPKD cases. However, due to the mild phenotype presentation of patients with mutations in GANAB, it is possible that this account for a larger proportion of the missing genetic causes of ADPKD and may be underdiagnosed.
