Pseudohypoaldosteronism type 2 (PHA2), also known as Gordon syndrome, is an inherited disease that causes high blood pressure and high levels of potassium in the blood. Recent studies have identified mutations in two genes (WNK1 and WNK4) as causes of PHA2.
Although disease-causing WNK4 mutations are known to increase internalization of a cell surface protein known as ROMK1 (which is involved in regulating potassium uptake) by kidney cells, the molecular details behind this increased internalization have not been clearly defined.
In a study that appears online on March 22 in advance of publication in the April print issue of the Journal of Clinical Investigation, Chou-Long Huang and colleagues from the University of Texas Southwestern Medical Center, Dallas, show that in vitro, rat WNK4 interacts with a protein known as ITSN and that this is important for WNK4-mediated internalization of ROMK1 by kidney cells. Furthermore, interactions between WNK4, ITSN, and ROMK1 were enhanced if WNK4 contained the PHA2-causing mutations, leading to increased ROMK1 internalization. This study therefore describes a molecular mechanism for the observation that disease-causing WNK4 mutations increase ROMK1 internalization by kidney cells.-Journal of Clinical Investigation
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