KLHL3

Pseudohypoaldosteronism type 2

At least 36 KLHL3 gene mutations have been found to cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). These mutations alter the KLHL3 protein, impairing its ability to attach to the E3 ubiquitin ligase complex or to WNK4. As a result, the complex is unable to tag WNK4 with ubiquitin, and degradation of the protein is impaired. An excess of WNK4 disrupts normal control of blood pressure, leading to hypertension and the other features of PHA2. It is unknown if WNK1 is affected by the abnormal E3 ubiquitin ligase complex or whether WNK1 plays a role in development of PHA2 caused by KLHL3 gene mutations.