Disease-causing genetic mutation reveals its molecular secrets

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