Gene defect that will lead to the clinical and biochemical profile of PHA 2
Several genes have been identified for the etiology of PHA 2. The first ones were two (With-No-Lysine [K]) kinases, WNK1, and WNK4, identified by linkage analysis using (large) pedigrees of affected families. These WNK kinases have multiple functions in the distal nephron, including regulation of the NCCT in the DCT via cascade of various kinases, including WNK3. In part, they are regulated by intracellular chloride concentration. When these kinases are mutated (WNK1: intronic gain-of-function deletions, WNK4: loss-of-function mutations), distal sodium reabsorption via NCCT is increased regardless of volume status, resulting in salt-sensitive hypertension. Mutations in the WNKs are believed to cause increased NCCT plasma membrane abundance and therefore increased activity. Another hallmark of PHA 2 is hyperkalemia; the mechanisms leading to decreased potassium excretion are complex and can be explained by WNK participation in determining the nature of aldosterone action, which has distinct functions in the setting of hypovolemia (sodium retention) and hyperkalemia (potassium excretion). The inhibition of potassium excretion despite marked hyperkalemia occurs likely by both, direct inhibition of the potassium channel renal outer medullary K (ROMK) (increased endocytosis) in the DCT and decreased potassium excretion in the collecting duct (CD; lower sodium concentration in the lumen leads to decreased diffusion gradient for movement of cellular potassium into the urine). The role of NCCT activation in the pathophysiology of PHA 2 explains why this condition is so responsive to treatment with thiazide diuretics.
Two more gene defects for PHA 2 have been identified by exome sequencing; Kelch-like 3 (KLHL3) and Cullin 3 (CUL3). These genes are expressed in the DCT and co-localize with WNK1, WNK4, and the NCCT. They form a complex, a KLHL3-CUL3 E3 ubiquitin ligase, which regulates WNK1 and WNK4 activity in the DCT in complex fashion and ubiquitination (deactivation) of NCCT from cell surface.
The phenotype of individuals affected by these different gene defects in PHA 2 differs. Patients with KLHL3 and CUL3 mutations appear more severely affected as they develop PHA 2 at younger age and present with more severe hyperkalemia and also a failure to thrive. Patients with WNK1 mutations have a milder phenotype, whereas patient with WNK4 mutations can feature hypercalciuria. However, thiazide diuretics are a very effective treatment of choice in all forms of PHA 2.