Inability to Experience Pain: Pathophysiology of the SCN11A disorder

• Applicant: Professor Dr. Ingo Kurth
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261885804

The ability to perceive and react to pain is essential to protect the body from injury. In the condition of Congenital Inability to Experience Pain self-mutilations, slow-healing wounds and painless bone fractures are the consequence of the lack to sense pain. We showed that loss of pain perception results from a specific missense mutation in SCN11A, which encodes the NaV1.9 voltage-gated sodium channel. This de novo mutation (p.Leu811Pro) was identified in independent individuals with the condition using whole-exome sequencing. SCN11A / NaV1.9 is expressed in nociceptors, specialized sensory nerves that transmit pain signals from the body periphery to the central nervous system. We engineered mice that carry the missense mutation in Scn11a and found that these animals have reduced sensitivity to pain. Knockin-mice showed self-inflicted tissue lesions, likewise recapitulating aspects of the human phenotype. Mutant NaV1.9 channels in sensory neurons of knockin-mice are functional, but display excessive activity at resting voltages and cause sustained depolarization of pain-sensing neurons. This gain-of-function in the basal activity of NaV1.9 may lead to progressive inactivation of other sodium and calcium channels, which then results in a conduction block and impaired signal transmission to the brain. The finding raises the possibility that manipulating NaV1.9 activity could be an alternative pathway to treat pain. To better understand the mechanism of disease we will here investigate whether noxious stimulation impairs spinal-cord neuron activation in-vivo. Furthermore, neurodegeneration as consequence of the chronic NaV1.9 dysfunction will be addressed since accompanying neuron loss would clearly argue against meaningful NaV1.9-related drug application in pain therapy. Patients harboring the SCN11A mutation showed severe gastrointestinal motility disturbances, which might be caused by dysfunction of intestinal pacemaker neurons. This will be addressed in the existing mouse model. Moreover, two additional mouse models will be generated to analyze whether the development of nociceptive circuits is already impaired by NaV1.9 gain of function. The general impact of TTX-resistant NaV1.8 and NaV1.9 currents for neuronal excitability will also be clarified.

• DFG Programme: Research Grants