Loss of SLC9A6/NHE6 impairs nociception in a mouse model of Christianson syndrome

Pain. 2020 Nov;161(11):2619-2628. doi: 10.1097/j.pain.0000000000001961.


Children diagnosed with Christianson syndrome (CS), a rare X-linked neurodevelopmental disorder characterized by intellectual disability, epilepsy, ataxia, and mutism, also suffer from hyposensitivity to pain. This places them at risk of sustaining serious injuries that often go unattended. Christianson syndrome is caused by mutations in the alkali cation/proton exchanger SLC9A6/NHE6 that regulates recycling endosomal pH homeostasis and trafficking. Yet, it remains unclear how defects in this transporter lead to altered somatosensory functions. In this study, we validated a Nhe6 knockout (KO) mouse as a model of CS and used it to identify the cellular mechanisms underlying the elevated pain tolerance observed in CS patients. Within the central nervous system, NHE6 immunolabelling is detected in a small percentage of cortical neurons involved in pain processing, including those within the primary somatosensory and the anterior cingulate cortices as well as the periaqueductal gray. Interestingly, it is expressed in a larger percentage of nociceptors. Behaviourally, Nhe6 KO mice have decreased nocifensive responses to acute noxious thermal, mechanical, and chemical (ie, capsaicin) stimuli. The reduced capsaicin sensitivity in the KO mice correlates with a decreased expression of the transient receptor potential channel TRPV1 at the plasma membrane and capsaicin-induced Ca influx in primary cultures of nociceptors. These data indicate that NHE6 is a significant determinant of nociceptor function and pain behaviours, vital sensory processes that are impaired in CS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia*
  • Capsaicin
  • Epilepsy*
  • Genetic Diseases, X-Linked*
  • Humans
  • Intellectual Disability*
  • Mice
  • Mice, Inbred C57BL
  • Microcephaly*
  • Nociception
  • Nociceptors
  • Ocular Motility Disorders*
  • Sodium-Hydrogen Exchangers
  • TRPV Cation Channels


  • NHE6 protein, mouse
  • Sodium-Hydrogen Exchangers
  • TRPV Cation Channels
  • Capsaicin

Supplementary concepts

  • Mental Retardation, X-Linked, Syndromic, Christianson Type