WNK1

Mutations in the WNK1 gene are responsible for one type of hereditary sensory and autonomic neuropathy type II (HSAN2) called HSAN2A. People with HSAN2A lose the ability to feel pain or sense hot and cold. More than a dozen mutations in the WNK1 gene have been identified in people with HSAN2A. All of these mutations lead to an abnormally shortened WNK1/HSN2 protein that is probably nonfunctional. People with HSAN2A have a reduction in the number of sensory neurons; however, the role that the abnormal WNK1/HSN2 protein plays in that loss is unclear. The loss of sensory neurons results in the signs and symptoms of HSAN2A.

WNK1 gene mutations involved in HSAN2A do not appear to affect the L-WNK1 or KS-WNK1 isoforms.

At least two mutations in the WNK1 gene 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). The mutations involved in this condition delete large numbers of DNA building blocks (nucleotides) from the WNK1 gene. These deletions lead to increased activity of the WNK1 gene and excess L-WNK1 protein. An increase in L-WNK1 protein abnormally increases sodium reabsorption and blocks potassium secretion, resulting in hypertension and hyperkalemia.

WNK1 gene mutations involved in PHA2 do not appear to affect the KS-WNK1 or WNK1/HSN2 isoforms.

Studies have associated normal variations in the WNK1 gene with an increased risk of high blood pressure (hypertension) in people without PHA2 (described above). A combination of genetic variations and environmental factors likely influence the development of this complex condition.