Key result
KLHL3 knockout mice exhibited increased WNK1 and WNK4 expression in the kidney and PHAII-like phenotypes compared to heterozygous mice, indicating a dominant negative effect of mutant KLHL3.
This preclinical study demonstrates that autosomal dominant PHAII is caused by a dominant negative effect of mutant KLHL3, as heterozygous deletion alone does not produce the disease phenotype.
KLHL3-dominant negative effects in mice extend preclinical PHAII models; leaves open human validation before any clinical implications.
Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, kelch-like 3 (KLHL3), and cullin3 (CUL3) genes are known to cause the hereditary disease pseudohypoaldosteronism type II (PHAII). It was recently demonstrated that this results from the defective degradation of WNK1 and WNK4 by the KLHL3/CUL3 ubiquitin ligase complex. However, the other physiological in vivo roles of KLHL3 remain unclear. Therefore, here we generated KLHL3−/− mice that expressed β-galactosidase (β-Gal) under the control of the endogenous KLHL3 promoter. Immunoblots of β-Gal and LacZ staining revealed that KLHL3 was expressed in some organs, such as brain. However, the expression levels of WNK kinases were not increased in any of these organs other than the kidney, where WNK1 and WNK4 increased in KLHL3−/− mice but not in KLHL3+/− mice. KLHL3−/− mice also showed PHAII-like phenotypes, whereas KLHL3+/− mice did not. This clearly demonstrates that the heterozygous deletion of KLHL3 was not sufficient to cause PHAII, indicating that autosomal dominant type PHAII is caused by the dominant negative effect of mutant KLHL3. We further demonstrated that the dimerization of KLHL3 can explain this dominant negative effect. These findings could help us to further understand the physiological roles of KLHL3 and the pathophysiology of PHAII caused by mutant KLHL3.
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Sasaki et al. (2017) studied Pseudohypoaldosteronism type II (PHAII). KLHL3 knockout (KLHL3-/-) vs. KLHL3 heterozygous (KLHL3+/-) was evaluated on WNK kinase expression and PHAII-like phenotypes. KLHL3 knockout mice exhibited increased WNK1 and WNK4 expression in the kidney and PHAII-like phenotypes compared to heterozygous mice, indicating a dominant negative effect of mutant KLHL3.
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