A de novo gain-of-function mutation in SCN11A causes loss of pain perception

Abstract

The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.

The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P

“…Both had recurrent injuries and self-mutilations secondary to feeling no pain, and identical de novo heterozygous p.L811P variants in the voltage-gated sodium channel Na V 1.9, encoded by SCN11A. 4 We have now identified a further case with the identical variant c.2432T4C (p.(L811P)) and report that all have a complex extended phenotype, see Table 1.…”

“…Remarkably this was at the same location as seen in transgenic Scn11a-mutant mice. 4 Ulceration and itching may be secondary to hyperhidrosis, as itching only reduced following the use of cyprohepatidine, which lead to a clear reduction in sweating. Hyperhidrosis persisted throughout life, and increased on exertion and raised ambient temperatures.…”

“…6,7 All mutations including p.L811P show gain-offunction properties at a channel level and suggest neuron hyperexcitability. 4,6,7 Yet the contrary physiological outcome depending on the variant, that is, increased versus abolished pain perception, remains puzzling. One explanation might be the effect size of the respective mutation on Na V 1.9 function that determines the physiological consequences.…”

“…Carriers' frequency for different loss-of-function GJB2 mutations is very high worldwide (up to 3%), 1 suggesting a heterozygous advantage for a global condition or a founder effect. 2 In this light, epidermal thickening in GJB2 carriers 3,4 has been proposed as a possible advantage reducing infections and bacterial invasion through skin. 5,6 Moreover, in vitro functional studies demonstrated that the loss-of-functional GJB2 expression provides improved protection against gastrointestinal bacterial pathogens.…”

Axon Transport and Neuropathy

“…They were originally subdivided into five types (HSAN1 to HSAN5) on the basis of distinct clinical signs and symptoms. 76 The molecular and clinical classification of these diseases has evolved to include two more recently recognized types (HSAN6 and HSAN7) 77,78 and many pathogenic germline mutations in >16 genes which cause both AD and AR forms of HSAN (recently reviewed in detail 79,80 ). The mechanisms by which mutations in many functionally diverse genes disrupt neuron development and innervation homeostasis in HSAN are generally poorly understood.…”