Further evidence for functional recovery of AQP2 mutations associated with nephrogenic diabetes insipidus.

ABSTRACT

Aquaporin-2 (AQP2) is a homotetrameric water channel responsible for the final water reuptake in the kidney. Disease-causing AQP2 mutations induce nephrogenic diabetes insipidus (NDI), a condition that challenges the bodily water balance by producing large urinary volumes. In this study, we characterize three new AQP2 mutations identified in our lab from NDI patients (A120D, A130V, T179N) along the previously reported A47V variant. Using Xenopus oocytes, we compared the key functional and biochemical features of these mutations against classical recessive (R187C) and dominant (R254Q) forms, and once again found clear functional recovery features (increased protein stability and function) for all mutations under study. This behaviour, attributed to heteromerization to wt-AQP2, challenge the classical model to NDI which often depicts recessive mutations as ill-structured proteins unable to oligomerize. Consequently, we propose a revised model to the cell pathophysiology of AQP2-related NDI which accounts for the functional recovery of recessive AQP2 mutations.