CUL3 – Pseudohypoaldosteronism Type II

Pseudohypoaldosteronism type II (PHA II), also known as Gordon syndrome, is a rare autosomal dominant renal tubular disorder marked by hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and low renin levels. Mutations in CUL3 (HGNC:2553) disrupt Cullin-3 function within Cullin-RING E3 ubiquitin ligase (CRL3) complexes, perturbing renal electrolyte handling and blood pressure regulation. Genetic defects in CUL3 underlie a severe, early-onset form of PHA II.

Exome sequencing in 41 unrelated PHA II families identified heterozygous CUL3 mutations, predominantly de novo, all resulting in in-frame skipping of exon 9 ([PMID:22266938]). A literature review of 46 molecularly diagnosed PHA II cases documented CUL3 variants in 9 probands, including 11 familial and 16 sporadic presentations ([PMID:37081692]). Segregation in multiplex families corroborates pathogenicity.

CUL3 variant spectrum is dominated by splice-site alterations causing loss of the exon 9-encoded segment of CUL3, with occasional missense alleles such as c.1376A>T (p.Lys459Met) reported in a juvenile patient whose hypertension and electrolyte abnormalities normalized on thiazide therapy ([PMID:35703886]). These variants impair CUL3’s scaffold function for BTB-domain adaptors, notably KLHL3.

Mechanistically, CRL3^KLHL3 ubiquitinates WNK1 and WNK4 kinases to regulate the Na^+-Cl^− cotransporter (NCC). CUL3–KLHL3 complexes with PHA II-causing mutations exhibit reduced WNK ubiquitination, leading to elevated WNK levels and NCC hyperactivation ([PMID:23387299]). Moreover, the CUL3 Δ403–459 mutant shows enhanced neddylation and selectively degrades KLHL3, further stabilizing WNK kinases in cells ([PMID:25250572]).

Animal and cellular models support haploinsufficiency and dominant-negative effects. Knock-in mice carrying a Cul3 intron 8 splice mutation display PHA II-like electrolyte and blood pressure phenotypes, and vascular smooth muscle-specific Cul3 deletion elevates RhoA signaling and contributes to hypertension ([PMID:30967423]; [PMID:26490675]).

Integration of genetic and functional data meets criteria for a Definitive gene–disease relationship. CUL3 mutations consistently produce PHA II through loss of CRL3-mediated WNK regulation, and thiazide diuretics effectively reverse the phenotype. Genetic testing for CUL3 variants informs early diagnosis and targeted therapy.

Key Take-home: CUL3 variant analysis is essential for diagnosing PHA II, guiding thiazide treatment, and preventing long-term cardiovascular and renal complications.

References

• Nature • 2012 • Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. PMID:22266938
• Endocrine Journal • 2023 • Classification of pseudohypoaldosteronism type II as type IV renal tubular acidosis: results of a literature review. PMID:37081692
• The Biochemical Journal • 2013 • The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. PMID:23387299
• The Journal of Clinical Investigation • 2014 • Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3. PMID:25250572
• Journal of Hypertension • 2022 • A case of novel mutation of Cullin 3 gene in pseudohypoaldosteronism type II. PMID:35703886

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