KLHL3 – Pseudohypoaldosteronism Type 2D

Pseudohypoaldosteronism Type 2D (PHAII D) is a rare autosomal recessive syndrome characterized by hypertension, hyperkalemia, metabolic acidosis, and hypercalciuria. Initial description in a 16-year-old girl demonstrated severe hypertension (220/110 mmHg), hyperkalemia, normal anion gap metabolic acidosis and hypercalciuria responsive to thiazide diuretics (PMID:29482694). The condition is caused by biallelic or, less commonly, dominant-negative mutations in KLHL3, a BTB-BACK-Kelch substrate adaptor for CUL3 ubiquitin ligase, leading to dysregulated ion transport in the distal nephron.

Genetic evidence for KLHL3 in PHAII D includes linkage analysis and whole-exome sequencing in two pedigrees, followed by direct sequencing of 43 additional affected individuals identifying 11 missense variants in Kelch repeats (PMID:22406640). In a multinational cohort of 153 cases (84 probands, 69 relatives), 50 carried pathogenic KLHL3 variants, with recessive inheritance observed in 14 of 50 KLHL3-related probands and no KLHL3 variants in unaffected family members (PMID:34622103).

Segregation analysis revealed 69 affected relatives harboring KLHL3 mutations consistent with autosomal recessive transmission and full penetrance in homozygotes (PMID:34622103). Case series total at least 127 unrelated probands across >10 families, with consistent co-segregation of KLHL3 variants and disease phenotype.

The variant spectrum is dominated by missense substitutions clustering in BTB, BACK and Kelch domains, with occasional splice and truncating alleles. A recurrent allele, c.1229C>T (p.Ser410Leu), has been identified in unrelated families (PMID:23962426). Hypomorphic and deep-intronic alleles have not been reported to date.

Mechanistically, PHAII D-causing KLHL3 mutations impair assembly of the KLHL3–CUL3 E3 ligase complex and reduce ubiquitination of WNK kinases. Co-immunoprecipitation and cycloheximide chase assays in HEK293T cells showed that mutations such as p.Ser410Leu and p.Arg528His decrease KLHL3 stability, CUL3 binding and WNK4 ubiquitination, leading to WNK4 accumulation and enhanced NCC activation (PMID:23962426).

In vivo, KLHL3(R528H/+) knock-in mice recapitulate salt-sensitive hypertension, hyperkalemia and metabolic acidosis with elevated WNK1/4 and NCC phosphorylation (PMID:24821705). KLHL3–/– mice exhibit PHAII-like phenotypes only in homozygotes, confirming a dominant-negative mechanism in heterozygotes (PMID:28052936).

Overall, the evidence for KLHL3 in PHAII D is Definitive, supported by >100 probands, multi-family segregation, and concordant functional and animal model data. Genetic testing for KLHL3 variants informs diagnosis, guides thiazide therapy, and enables family counseling. Key take-home: KLHL3 mutation screening is clinically actionable in suspected PHAII D to confirm molecular diagnosis and direct targeted therapy.

References

• Nature Genetics • 2012 • KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. PMID:22406640
• Kidney International Reports • 2021 • The variety of genetic defects explains the phenotypic heterogeneity of Familial Hyperkalemic Hypertension. PMID:34622103
• Biochemical and Biophysical Research Communications • 2013 • Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms. PMID:23962426
• Human Molecular Genetics • 2014 • Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice. PMID:24821705
• Molecular and Cellular Biology • 2017 • KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3. PMID:28052936
• Journal of the College of Physicians and Surgeons--Pakistan : JCPSP • 2018 • Pseudohypoaldosteronism Type II: A Young Girl Presented with Hypertension, Hyperkalemia and Metabolic Acidosis. PMID:29482694

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