KLHL3 Gene: Kelch-Like Family Member 3 – Pseudohypoaldosteronism Type II (PHA2D) and Blood Pressure Regulation
A comprehensive biomedical overview of KLHL3, its genomic context, protein function, associated diseases, expression patterns, and mutational landscape.
Gene Information Card
| Symbol | KLHL3 |
|---|---|
| Full Name | Kelch-like family member 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 5q31.2 |
| NCBI Gene ID | 26249 ncbi.nlm.nih.gov/gene/26249 |
| Ensembl ID | ENSG00000172572 |
| UniProt ID | Q9UH77 |
| OMIM ID | 605775 |
| HGNC ID | 6355 |
| Aliases | KIAA1387, kelch-like 3 |
Description
The KLHL3 gene encodes kelch-like family member 3, a substrate adaptor protein for Cullin3-based E3 ubiquitin ligase complexes. KLHL3 plays a critical role in the ubiquitination and degradation of WNK kinases (WNK1, WNK4), which are key regulators of sodium chloride cotransporter (NCC) in the distal nephron. Mutations in KLHL3 cause pseudohypoaldosteronism type II (PHA2D), an autosomal dominant or recessive form of familial hyperkalemic hypertension, characterized by hypertension, hyperkalemia, and metabolic acidosis. KLHL3 is also implicated in other cellular processes including cytoskeletal organization and cell signaling.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Pseudohypoaldosteronism type II (PHA2D) | Loss-of-function mutations impair KLHL3-mediated ubiquitination of WNK kinases, leading to WNK accumulation and overactivation of NCC, causing increased sodium reabsorption and hypertension. | OMIM: 605775; ClinVar; multiple publications (e.g., Boyden et al., 2012; Louis-Dit-Picard et al., 2012) |
| Hypertension (essential) | Common variants in KLHL3 may contribute to blood pressure regulation, though specific mechanisms are less defined. | GWAS studies (e.g., International Consortium for Blood Pressure Genome-Wide Association Studies) |
| Hyperkalemia (familial) | Same mechanism as PHA2D, leading to impaired potassium excretion. | OMIM: 605775 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Kidney | High (approx. 20-30 nTPM) | High expression in renal tubules, consistent with role in ion transport. |
| Liver | Moderate (approx. 10-15 nTPM) | Expression in hepatocytes, function unclear. |
| Brain | Low to moderate (approx. 5-10 nTPM) | Expression in various brain regions, potential role in neuronal signaling. |
| Heart | Low (approx. 3-5 nTPM) | Minimal expression, not a primary site. |
| Lung | Low (approx. 2-4 nTPM) | Low expression, no known specific function. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | High (approx. 30 nTPM) | Commonly used for functional studies of KLHL3. |
| HepG2 | Moderate (approx. 15 nTPM) | Liver carcinoma cell line, expresses KLHL3. |
| A549 | Low (approx. 5 nTPM) | Lung carcinoma cell line, low expression. |
| MCF7 | Low (approx. 3 nTPM) | Breast cancer cell line, low expression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1582C>T (p.Arg528Cys) | Missense | Rare (found in PHA2D families) | Loss-of-function: disrupts KLHL3 binding to Cullin3, impairing ubiquitination of WNK kinases. |
| c.1661G>A (p.Arg554His) | Missense | Rare (found in PHA2D families) | Loss-of-function: affects substrate recognition, leading to WNK accumulation. |
| c.1444C>T (p.Arg482Trp) | Missense | Rare (found in PHA2D families) | Loss-of-function: disrupts Kelch domain, impairing substrate binding. |
| c.1183C>T (p.Arg395Cys) | Missense | Rare (found in PHA2D families) | Loss-of-function: affects protein stability or interaction. |
| c.1666C>T (p.Arg556Cys) | Missense | Rare (found in PHA2D families) | Loss-of-function: similar to other Arg mutations in Kelch domain. |
Mutation functional classification
Loss of Function (LOF)
Most KLHL3 mutations causing PHA2D are loss-of-function, impairing the ability of KLHL3 to ubiquitinate WNK kinases, leading to WNK accumulation and overactivation of NCC.
Gain of Function (GOF)
No gain-of-function mutations have been reported for KLHL3 in disease context.
Dominant Negative (DN)
Some missense mutations may act in a dominant-negative manner, as PHA2D can be inherited in an autosomal dominant pattern. Mutant KLHL3 may interfere with wild-type function in the Cullin3 complex.
View complete mutation data：
Gene Ontology (GO)
| • Ubiquitin-protein transferase activity | • Protein binding |
| • Cytoskeleton organization | • Regulation of blood pressure |
| • Protein ubiquitination | • Ion transport |
| • Cellular response to stress |
Pathways
• WNK signaling pathway
• Regulation of sodium chloride cotransporter (NCC)
• Ubiquitin-proteasome pathway
• Cullin-RING E3 ligase pathway
Protein Summary
KLHL3 is a 587-amino acid protein containing an N-terminal BTB/POZ domain, a central BACK domain, and six C-terminal Kelch repeats. It functions as a substrate adaptor for Cullin3-based E3 ubiquitin ligase complexes, targeting WNK kinases (WNK1, WNK4) for ubiquitination and degradation. This regulation is essential for controlling the activity of the sodium chloride cotransporter (NCC) in the distal nephron. Mutations in KLHL3 disrupt this process, leading to pseudohypoaldosteronism type II (PHA2D). The protein is also involved in cytoskeletal organization and may have other substrates.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| KLHL32 Knockout HEK293 Cell Line | EDJ-KQ7463 | Human | 114792 | Details Get a Quote |
| KLHL33 Knockout HEK293 Cell Line | EDJ-KQ7497 | Human | 123103 | Details Get a Quote |
| KLHL3 Knockout HEK293 Cell Line | EDJ-KQ8482 | Human | 26249 | Details Get a Quote |
| KLHL31 Knockout HEK293 Cell Line | EDJ-KQ11631 | Human | 401265 | Details Get a Quote |
| KLHL34 Knockout HEK293 Cell Line | EDJ-KQ11867 | Human | 257240 | Details Get a Quote |
| KLHL30 Knockout HEK293 Cell Line | EDJ-KQ13960 | Human | 377007 | Details Get a Quote |
| KLHL35 Knockout HEK293 Cell Line | EDJ-KQ13961 | Human | 283212 | Details Get a Quote |
| KLHL36 Knockout HEK293 Cell Line | EDJ-KQ13962 | Human | 79786 | Details Get a Quote |
| KLHL38 Knockout HEK293 Cell Line | EDJ-KQ13963 | Human | 340359 | Details Get a Quote |
| KLHL32 Knockout HCT 116 Cell Line | EDJ-KQ32682 | Human | 114792 | Details Get a Quote |
| KLHL36 Knockout A-549 Cell Line | EDJ-KQ42616 | Human | 79786 | Details Get a Quote |
| KLHL35 Knockout A-549 Cell Line | EDJ-KQ43891 | Human | 283212 | Details Get a Quote |
| KLHL35 Knockout HCT 116 Cell Line | EDJ-KQ43892 | Human | 283212 | Details Get a Quote |
| KLHL35 Knockout HeLa Cell Line | EDJ-KQ43893 | Human | 283212 | Details Get a Quote |
| KLHL36 Knockout HCT 116 Cell Line | EDJ-KQ43895 | Human | 79786 | Details Get a Quote |
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