Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis

Area of Science:

• Genetics
• Nephrology
• Molecular Biology

Background:

• Familial hyperkalemic hypertension (FHHt) is linked to mutations in WNK1, WNK4, and KLHL3-CUL3 genes.
• WNK proteins are crucial for renal ion transport, and their cellular degradation is important.

Purpose of the Study:

• Identify novel genetic variants associated with FHHt.
• Investigate the functional impact of these variants on WNK1 isoforms and renal function.

Main Methods:

• Whole exome and targeted sequencing identified new WNK1 variants.
• Functional studies in Xenopus oocytes and HEK293T cells assessed ubiquitination.
• CRISPR/Cas9 mouse model development and renal investigations were performed.

Main Results:

• New WNK1 variants were found in a conserved motif interacting with KLHL3-CUL3.
• Mutations reduced ubiquitination of the KS-WNK1 isoform, not L-WNK1.
• A mouse model showed hyperkalemic hyperchloremic phenotype and altered SPAK-NCC and ROMK activity.

Conclusions:

• These WNK1 variants highlight the critical role of KS-WNK1 isoform regulation in potassium homeostasis.
• Disruption of KS-WNK1 degradation by KLHL3-CUL3 leads to FHHt-like phenotypes.
• Understanding these mechanisms offers insights into renal ion transport disorders.