Type 2 pseudohypoaldosteronism (Gordon syndrome) (Pseudohypoaldosteronism type 2) - Genes WNK1, WNK4 Cul3 or KLHL3

Type 2 pseudohypoaldosteronism (PHA II), also known as syndrome or family Gordon hypertension and hyperkalemia syndrome, is a process characterized by problems in regulating the concentrations of sodium and potassium in the body. People with PHA II have hypertension and hyperkalemia despite having normal renal function. Usually, hyperkalemia occurs first, and hypertension develops later. Affected individuals may also have hyperchloraemia, hypercalcemia and metabolic acidosis in blood. People with hyperkalemia, and metabolic acidosis hyperchloraemia may show nonspecific symptoms such as nausea, vomiting, fatigue and muscle weakness.

The PHA II may occur as a result of mutations in the gene WNK1 (WNK lysine deficient protein kinase 1), WNK4 (WNK lysine deficient protein kinase 4), Cul3 (cullin 3), or KLHL3 (kelch like family member 3). These genes play a role in regulating blood pressure.

The WNK1 gene, located on the short arm of chromosome 12 (12p13.3), encoding multiple protein isoforms WNK1. The different isoforms WNK1 are important in several functions in the body, including regulating blood pressure and pain sensation. The WNK4 gene, located on the long arm of chromosome 17 (17q21.2,) encodes a kinase that, like WNK1 kinase plays a role in regulating blood pressure. Kinase WNK1 is a regulator of blood pressure controls the transport of sodium and chloride, while the kinase WNK4 is especially present in the kidney, regulating the balance between resorption of NaCl and potassium secretion by inhibiting the NCC activity (thiazide sensitive NaCl cotransporter-).

Have identified at least two mutations in the gene WNK1 eight mutations in the gene WNK4 in people with type 2 pseudohypoaldosteronism (PHA II). Mutations in the gene increase WNK1 gene activity and lead to an excess of protein WNK1. Excess protein abnormally increases sodium reabsorption and potassium secretion blocks. These effects lead to increased concentrations of sodium and potassium in the body, leading to hypertension and hyperkalemia, due to increased activity of NCC. Although the exact mechanism is unknown, it is also suspected that WNK1 is involved in activation of epithelial sodium channel (ENaC), involved in the absorption of sodium and potassium excretion, also thereby contributing to hypertension and hyperkalemia . Therefore, the main symptoms of individuals with PHA II with mutations in the gene WNK1 result from increased activity of both ENaC as NCC. As mutations in the gene WNK4, these give rise to an abnormal protein that does not inhibit sodium channels, but inhibits potassium channel more tightly. These mutations increase in sodium reabsorption and decreased secretion of potassium, resulting in hypertension and hyperkalemia.

Signs of hypercalciuria also been found in patients with mutations in the WNK4 gene, so that increased activity of the NCC may also be associated with excessive calcium removal, since these patients respond six times to treatment with thiazide that patients with hypercalciuria without PHA II. However, it has not found any patient with PHA II induced alterations in WNK1 gene with hypercalciuria, indicating that patients with mutations in the WNK1 gene is more relevant the increase in activity of ENaC the NCC.

The proteins encoded from Cul3 gene, located on the long arm of chromosome 2 (2q36.2) and KLHL3, located on the long arm of chromosome 5 (5q31) help regulate the amount of protein available WNK1 and WNK4. Cullin-3 and KLHL3 are two units of ubiquitin ligase E3 complex which certain other proteins labeled ubiquitin molecules. This acts as a signal molecule for labeling proteins are degraded when no longer needed. Ubiquitin acts as a signal for the proteasome, which bind to labeled proteins and degrades. The system ubiquitin- proteasome of the system acts as quality control of the cell by eliminating damage, defects, and excess protein. This system also regulates the concentration of proteins involved in several critical cellular activities, such as the timing of cell division and growth. E3 ubiquitin ligases that contain Cullina-3 and KLHL3 are able to label proteins WNK4 WNK1 and ubiquitin. These proteins are involved in controlling blood pressure in the body. By regulating the amount of WNK1 and WNK4 available, and KLHL3 cullin-3 play a role in controlling blood pressure.

They have identified at least 17 Cul3 gene mutations and 36 mutations in the gene KLHL3 in people with type 2 pseudohypoaldosteronism (PHA II). Mutations in genes Cul3 or alter KLHL3 cullin-3 and KLHL3 proteins, respectively, impairing their ability to attach to the ubiquitin ligase E3 complex or WNK4. As a result, the complex is not able to tag WNK4 ubiquitin and the degradation of the protein is affected. The effect of these mutations on protein WNK1 is unclear. Excess WNK4 likely alters the regulation of the concentrations of sodium and potassium, leading to hypertension and hyperkalemia.

Type 2 pseudohypoaldosteronism is inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. In most cases due to mutations in the gene WNK1, WNK4, or KLHL3, an affected person inherits the mutation from an affected parent. While some cases due to Cul3 genetic mutations can be inherited from an affected parent, many result from new mutations in the gene and occur in people with no history of disease in your family. Some cases due to mutations in the gene KLHL3 are inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with type 2 pseudohypoaldosteronism (PHA II), by complete PCR amplification of the exons of the genes WNK1, WNK4 Cul3 or KLHL3, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).