KLHL3 and Pseudohypoaldosteronism Type II

Recent studies have established a strong association between variants in KLHL3 and pseudohypoaldosteronism type II, a renal tubular disorder characterized by hyperkalemia, metabolic acidosis, and hypertension (PMID:27780982, PMID:22266938). Multiple independent case reports have documented affected probands with both autosomal dominant and autosomal recessive inheritance patterns. In several families, segregation studies confirmed that affected relatives also harbor KLHL3 mutations, lending further credence to the gene–disease relationship (PMID:35093948).

Genetic evidence is robust, with a recurring mutational spectrum that includes pathogenic variants such as c.1291C>T (p.Arg431Trp). This variant, along with others identified in distinct cohorts, has been observed in affected individuals and segregates with the phenotype in multi‑generational families (PMID:29482694). Overall, the identification of KLHL3 mutations in diverse populations underscores the clinical relevance of this gene in pseudohypoaldosteronism type II.

Functional studies further support the causal role of KLHL3 by demonstrating that mutations impair the formation or stability of the KLHL3–Cullin3 E3 ubiquitin ligase complex. This disruption impedes the ubiquitination and subsequent degradation of WNK kinases, thereby leading to abnormal regulation of electrolyte transport in the distal nephron. In vitro assays and molecular dynamics simulations have confirmed that mutant KLHL3 proteins display reduced binding to their partners, providing a mechanistic explanation for the hypertensive and hyperkalemic phenotype (PMID:23962426).

Additional experimental evidence has shown that decreased ubiquitination of WNK kinases results in their accumulation, which overactivates the thiazide-sensitive NaCl cotransporter. This biochemical perturbation is directly linked to the clinical presentation of pseudohypoaldosteronism type II, and thiazide diuretics have been demonstrated to effectively reverse the deleterious effects (PMID:22266938).

Despite some variability in inheritance—with both dominant and recessive mutations reported—the convergence of genetic, segregation, and functional data supports a strong gene–disease association. The comprehensive data from both case reports and multi‑patient studies suggest that KLHL3 plays a key role in maintaining electrolyte homeostasis and blood pressure regulation.

Key take‑home sentence: KLHL3 mutations are clinically actionable markers for pseudohypoaldosteronism type II, providing a direct route for tailored management and therapeutic intervention.

References

• Clinical Pediatric Endocrinology • 2016 • A patient with pseudohypoaldosteronism type II complicated by congenital hypopituitarism carrying a KLHL3 mutation PMID:27780982
• Nephron • 2022 • A Novel Homozygous KLHL3 Mutation as a Cause of Autosomal Recessive Pseudohypoaldosteronism Type II Diagnosed Late in Life PMID:35093948
• Journal of the College of Physicians and Surgeons–Pakistan • 2018 • Pseudohypoaldosteronism Type II: A Young Girl Presented with Hypertension, Hyperkalemia and Metabolic Acidosis PMID:29482694
• Nature • 2012 • Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities PMID:22266938
• Biochemical and Biophysical Research Communications • 2013 • Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms PMID:23962426

Evidence Based Scoring (AI generated)