We performed a comprehensive genetic analysis for major inherited kidney diseases with next-generation sequencing including the genes responsible for PHA2 (WNK1, WNK4, KLHL3, and CUL3).
The Kelch-like 3 ( KLHL3) mutations contributed to the most common causative genes in patients with pseudohypoaldosteronism type II (PHAII); however, the molecular mechanisms of PHAII-causing mutations in BTB domain of KLHL3 in vivo have not been investigated.
Many PHAII-causing mutations are located in the Kelch domain of KLHL3 that binds with WNK4; however, detailed mechanisms by which these mutations disrupt the binding are not well-understood.
Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), and Cullin3 (CUL3) genes were identified as being responsible for hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII).
Interaction between the acidic motif (AM) of protein kinase WNK4 and the Kelch domain of KLHL3 are involved in the pathogenesis of pseudohypoaldosteronism type II, a hereditary form of hypertension.
This clearly demonstrates that the heterozygous deletion of <i>KLHL3</i> was not sufficient to cause PHAII, indicating that autosomal dominant type PHAII is caused by the dominant negative effect of mutant KLHL3.
Recent advancements in genetics, in particular whole-exome sequencing, have revealed that mutations in two additional genes encoding for KLHL3 and Cyllin3 also cause PHAII.
The findings of the present study also emphasize that the missense mutations in WNK4 that cause Gordon's syndrome strongly inhibit interaction with KLHL3.
Variants within at least four genes [i.e. with-no-lysine(K) kinase 1 (WNK1), WNK4, kelch-like family member 3 (KLHL3) and cullin 3 (CUL3)] can cause the phenotype of GS.
By MS and coimmunoprecipitation, we show that KLHL3 normally binds to WNK1 and WNK4, members of WNK (with no lysine) kinase family that have previously been found mutated in PHAII.
Therefore, the KLHL3 mutants causing PHAII investigated in this study exhibited less ability to ubiquitinate WNK4 because of KLHL3's low stability and/or decreased binding to CUL3 or WNK4.
Mutations in the gene of WNK family, especially in WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAII), characterized by hypertension.
Mutations in the gene of WNK family, especially in WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAII), characterized by hypertension.
Gain-of-function mutations of WNK1 and WNK4 in humans lead to a Mendelian hypertensive and hyperkalemic disease pseudohypoaldosteronism type II (PHAII).
We performed a comprehensive genetic analysis for major inherited kidney diseases with next-generation sequencing including the genes responsible for PHA2 (WNK1, WNK4, KLHL3, and CUL3).
Gain-of-function mutations of WNK1 and WNK4 in humans lead to a Mendelian hypertensive and hyperkalemic disease pseudohypoaldosteronism type II (PHAII).