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KLHL3 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

KLHL3 gene

The KLHL3 gene provides instructions for a protein that helps regulate blood pressure by controlling the degradation of specific proteins.

Normal Function

The KLHL3 gene provides instructions for making a protein that functions as part of the ubiquitin-proteasome system, the cell's quality control mechanism for breaking down unwanted or damaged proteins.

The KLHL3 protein is a component of an E3 ubiquitin ligase complex. This complex tags proteins with ubiquitin, signaling them for degradation by structures called proteasomes. Specifically, KLHL3 targets proteins called WNK1 and WNK4, which are involved in controlling blood pressure. By regulating the levels of these proteins, KLHL3 plays a critical role in blood pressure control.

Health Conditions Related to Genetic Changes

Pseudohypoaldosteronism type 2

At least 36 KLHL3 gene mutations have been found to cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia).

  • These mutations alter the KLHL3 protein, impairing its ability to attach to the E3 ubiquitin ligase complex or to WNK4.
  • As a result, the complex cannot tag WNK4 with ubiquitin, and the degradation of this protein is impaired.
  • An excess of WNK4 disrupts the normal control of blood pressure, leading to hypertension and the other features of PHA2.

Genomic Location

The KLHL3 gene is found on chromosome 5.

Frequently Asked Questions

Yes, KLHL3 mutations are inherited in an autosomal dominant pattern, meaning a single copy can cause disease. Asymptomatic relatives may carry the mutation and develop hypertension later in life. Genetic counseling and testing are recommended for first‑degree relatives, especially if they have a family history of early‑onset hypertension or unexplained hyperkalemia.
Standard antihypertensives such as thiazide diuretics or ACE inhibitors are often effective, but patients may also benefit from potassium‑sparing diuretics (e.g., amiloride) to counteract hyperkalemia. In some cases, a combination of a thiazide and a potassium‑sparing agent is used to achieve blood‑pressure control while maintaining normal potassium levels. Lifestyle measures—low‑salt diet, regular exercise, and weight management—are also essential.
Patients with PHA2 often notice high blood pressure that is difficult to control, especially in childhood or adolescence, and may experience muscle weakness or fatigue due to high potassium levels. A sudden rise in blood pressure during routine check‑ups, or unexplained episodes of dizziness, headache, or palpitations, can prompt a clinician to order a serum electrolyte panel and genetic testing for KLHL3 mutations.
Confirmation typically requires a blood or saliva sample for DNA extraction followed by targeted next‑generation sequencing or Sanger sequencing of the KLHL3 gene. The laboratory will look for pathogenic variants that alter the protein’s ability to bind WNK4 or the E3 ligase complex. Results are usually reported within 2–4 weeks and are interpreted by a clinical geneticist.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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