Grant: Project Grant

The ability to perceive pain is an evolutionary advantage aimed at protecting the host against potential injury. Defects in sensing pain as well as other types of external stimuli have been frequently observed in children with Christianson Syndrome (CS), and can lead to frequent injuries, self-mutilation, and shortened life expectancy. This syndrome is caused by loss-of-function mutations in the SLC9A6 gene encoding the pH-regulating alkali cation (sodium or potassium)/proton exchanger NHE6 isoform. How changes in the function of this protein lead to an elevated pain threshold, as well as other distortions in sensory perception, in CS patients is currently unknown. We hypothesize that these defects impair the proper pH and functioning of intracellular vesicles that carry neurotransmitter receptors and other ion channels to synapses of neurons, which in turn affects nervous system electrical activity and function, including the ability to sense pain. In the current project, we propose to combine clinical and basic science approaches, including a range of molecular, cellular, and electrophysiological techniques in cultured cells and genetically-engineered mouse models of this disorder, to understand the mechanisms underlying sensory dysfunction in CS patients. We also propose genetic mouse models and viral approaches to rescue NHE6 gene expression and determine whether complementation strategies can be a therapeutic option for these patients.