ISAP

In Europe one in five people is affected by chronic pain, causing a large socio-economic burden, with costs running in the billions. Almost half (40%) of chronic pain patients feels their pain management is inadequate, and there is a desperate need to develop new analgesic drugs. Pain is a complex trait influenced by many genetic factors. New large genome wide association studies (GWAS) have identified a number of genes associated with pain in humans. For many, their functional significance remains to be ascertained. Within one of the largest single site longitudinal cohorts with large pedigrees, familial history and genotypes in Europe (the CHRIS study), the Institute for Biomedicine has identified KCND3 to be associated with pain phenotypes. Through exome-sequencing the institute has recently identified 90 carriers of 9 missense and 1 frame-shift variants predicted to be damaging. Many of the carriers of these variants manifest moderate to severe chronic pain phenotypes. 
The protein encoded by KCND3 is responsible for subthreshold A-type K+ currents in sensory neurons, which can inhibit neuronal excitability below the threshold of action potential (AP). In rodent sensory neurons, KCND3 expression is enriched within the C-fiber low-threshold mechanoreceptors (C-LTMRs) population of cutaneous afferents, responsible for the detection of pleasant touch. Both KCND3 and C-LTMRs have been implicated in pre-clinical models of chronic pain. This has led us to the hypothesis, that the novel KCND3 variants are loss-of-function mutations, resulting in increased excitability of C-LTMRs, leading to abnormal pain. We identified one loss-of-function variant that in the homozygous state leads to unfunctional channels and a gain-of-function variant, that results in increased current density. Another mutant has unveiled a change in channel stability and alterations in channel kinetics which might underly a role in increased pain sensitivity. We will further investigate the role of this particular mutation in sensory neurons derived from its carriers or model systems constructed specifically. The novel insights gained about the impact of KCND3 variants in human peripheral pain processing are instrumental for the development of drugs targeting this potassium channel.