Kristopher Kahle MD PhD

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WNK1/HSN2: A novel kinase regulator of sensory transduction mutated in an orphan disease featuring congenital insensitivity to pain and temperature


The serine-threonine kinase WNK1 is unique in that mutations in two different isoforms of its encoding gene (PRKWNK1) cause separate orphan diseases, underscoring the critical and diverse role of this gene for human physiology1. A decade ago, mutations in the isoform of WNK1 predominantly expressed in kidney were detected in a rare inherited form of salt-sensitive hypertension called pseudohypoaldosteronism type 2 (PHA2). The molecular characterization of this disease made possible by study of a mouse model of the disease provided insight into the function of WNK1, helped improve the diagnosis and treatment of patients with PHA2, and also identified WNK1 as a novel potential target for the development of a novel class of antihypertensive drugs for the general population. Recently, mutations in a different isoform of WNK1 (termed “WNK1/HSN2”) have been detected in another orphan disease, hereditary sensory and autonomic neuropathy type 2 (HSAN2). This disease is a devastating neuropathy with early childhood onset, characterized by a progressively-reduced sensation to pain, temperature, and touch, leading to ulcerations of the hands/feet that often require amputations5. Currently, the pathogenesis of HSAN2 is unknown and there is no cure. Interestingly, WNK1/HSN2 is expressed exclusively in the spinal cord and peripheral nervous system; however, the upstream regulators, downstream molecular targets, and the mechanism by which mutations in WNK1/HSN2 cause disease all remain unknown. A mouse model of HSAN2 harboring disease-causing mutations in WNK1/HSN2 would be a valuable tool to test different models of disease pathogenesis, as well as to evaluate future therapies. We now have such a model and wish to characterize it in detail using a battery of histopathological, neurobehavioral, and electrophysiological assays in an effort to develop a mouse model of HSAN2. We anticipate this work will shed light into the normal function of WNK1/HSN2 and help define the molecular pathogenesis of HSAN2 to provide a basis for rational therapeutic intervention. Moreover, insights from these studies may benefit other more common neuropathies with similar characteristics as HSAN2, such as diabetic, HIV- and Hepatitis C-related neuropathies, as well as other complex pain syndromes.

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