Slc9a6, encoding the alkali cation/proton exchanger NHE6, regulates recycling endosomal pH homeostasis and trafficking. This function is crucial for normal cellular processes, and the gene is implicated in multiple biological pathways related to neuronal development and function [2,3]. Genetic models, such as knockout mouse models, are valuable for studying Slc9a6.

In the shaker rat, a naturally occurring Slc9a6 mutation (XM_217630.9 (Slc9a6):c.[191_195delinsA]) leads to progressive ataxia due to Purkinje cell loss. Adeno-associated virus (AAV)-based gene therapy targeting Slc9a6 expression to Purkinje cells reduces the shaker motor, molecular, and cellular phenotypes, suggesting potential therapeutic strategies for Christianson syndrome, which is also caused by Slc9a6 mutations [1]. In a Nhe6 knockout mouse model of Christianson syndrome, loss of Slc9a6/NHE6 impairs nociception. Nhe6 KO mice have decreased nocifensive responses to acute noxious thermal, mechanical, and chemical stimuli, and reduced capsaicin sensitivity due to decreased TRPV1 expression at the plasma membrane in nociceptors [3].

In conclusion, Slc9a6 is essential for maintaining normal endosomal function, which is vital for neuronal development and pain-related sensory processes. The use of gene-knockout mouse models, like those in the shaker rat and Nhe6 knockout mouse, has significantly contributed to understanding Slc9a6's role in ataxia and Christianson syndrome-related phenotypes, potentially guiding future therapeutic development for these conditions.

References:

1. Figueroa, Karla P, Anderson, Collin J, Paul, Sharan, Scoles, Daniel R, Pulst, Stefan M. . Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat. In Human molecular genetics, 32, 1647-1659. doi:10.1093/hmg/ddad004. https://pubmed.ncbi.nlm.nih.gov/36621975/

2. He, Hailan, Zhang, Huiwen, Chen, Hui, Zou, Xiaomin, Peng, Jing. 2023. Functional analysis of two SLC9A6 frameshift variants in lymphoblastoid cells from patients with Christianson syndrome. In CNS neuroscience & therapeutics, 29, 4059-4069. doi:10.1111/cns.14329. https://pubmed.ncbi.nlm.nih.gov/37381736/

3. Petitjean, Hugues, Fatima, Tarheen, Mouchbahani-Constance, Stephanie, Orlowski, John, Sharif-Naeini, Reza. . Loss of SLC9A6/NHE6 impairs nociception in a mouse model of Christianson syndrome. In Pain, 161, 2619-2628. doi:10.1097/j.pain.0000000000001961. https://pubmed.ncbi.nlm.nih.gov/32569089/