Scn11a, which encodes the voltage-gated sodium channel NaV1.9, is mainly expressed in peripheral nociceptive neurons. It is a key determinant of nociceptor excitability in primary sensory neurons, playing a crucial role in pain signalling pathways [2,5,6,7,8]. Mutations in Scn11a can lead to abnormal pain sensations, making it an important gene in understanding pain-related biological processes. Genetic models, such as gene knockout mouse models, can be valuable in further exploring its functions.

In a Nav1.9 knockout (KO) ICR mouse model, deletion of the Scn11a gene caused sensorineural hearing loss. The number of presynaptic CtBP2 puncta and spiral ganglion neurons (SGNs) in the basal turn were significantly lower in KO mice compared to wild-type mice. Additionally, KO mice showed higher and progressive elevated auditory brainstem response (ABR) threshold at 16 kHz and a significant increase in compound action potential (CAP) thresholds, indicating that Scn11a plays a role in regulating the function of ribbon synapses and auditory nerves [4]. In human studies, pathogenic or likely pathogenic variants of Scn11a were found in 19.8% of Japanese patients with familial episodic pain syndrome (FEPS), suggesting its involvement in this early-childhood-onset pain disorder [2]. Higher SCN11A mRNA levels were detected in iPSC-derived neurons from bipolar disorder (BD) patients and in peripheral blood mononuclear cells (PBMCs) of female BD patients with no records of alcohol dependence, psychosis, or suicide attempts, indicating a possible association with certain BD sub-phenotypes [3]. Also, in major depressive disorder (MDD) patients, SCN11A levels were increased, and there was an inverse relationship with total cholesterol (TC) levels, suggesting it may be a link between low lipid levels and MDD [1].

In conclusion, Scn11a is essential for normal function in the auditory system and pain-related neural pathways. Mouse KO models have revealed its role in sensorineural hearing loss, and human genetic studies have shown its association with various pain-related disorders, bipolar disorder, and major depressive disorder. These findings contribute to our understanding of the biological functions of Scn11a and its potential as a biomarker or therapeutic target in these disease areas.

References:

1. Xu, Ke, Zhao, Shuang, Ren, Yi, Chen, Jianjun, Xie, Peng. 2024. Elevated SCN11A concentrations associated with lower serum lipid levels in patients with major depressive disorder. In Translational psychiatry, 14, 202. doi:10.1038/s41398-024-02916-w. https://pubmed.ncbi.nlm.nih.gov/38734669/

2. Noguchi, Atsuko, Tezuka, Tohru, Okuda, Hiroko, Koizumi, Akio, Takahashi, Tsutomu. 2024. Genetic Analysis of SCN11A, SCN10A, and SCN9A in Familial Episodic Pain Syndrome (FEPS) in Japan and Proposal of Clinical Diagnostic Criteria. In International journal of molecular sciences, 25, . doi:10.3390/ijms25136832. https://pubmed.ncbi.nlm.nih.gov/38999942/

3. Voinsky, Irena, McCarthy, Michael J, Shekhtman, Tatyana, Kelsoe, John R, Gurwitz, David. 2019. SCN11A mRNA levels in female bipolar disorder PBMCs as tentative biomarker for distinct patient sub-phenotypes. In Drug development research, 80, 1128-1135. doi:10.1002/ddr.21598. https://pubmed.ncbi.nlm.nih.gov/31498915/

4. Zu, Mian, Guo, Wei-Wei, Cong, Tao, Shi, Wei-Guo, Yang, Shi-Ming. 2021. SCN11A gene deletion causes sensorineural hearing loss by impairing the ribbon synapses and auditory nerves. In BMC neuroscience, 22, 18. doi:10.1186/s12868-021-00613-8. https://pubmed.ncbi.nlm.nih.gov/33752606/

5. Baker, Mark D, Nassar, Mohammed A. 2020. Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels. In Pflugers Archiv : European journal of physiology, 472, 865-880. doi:10.1007/s00424-020-02419-9. https://pubmed.ncbi.nlm.nih.gov/32601768/

6. Chan, Amanda C Y, Kumar, Shivaram, Tan, Grace, Sharma, Vijay Kumar, Lai, Poh San. 2022. Expanding the genetic causes of small-fiber neuropathy: SCN genes and beyond. In Muscle & nerve, 67, 259-271. doi:10.1002/mus.27752. https://pubmed.ncbi.nlm.nih.gov/36448457/

7. Klein-Weigel, Peter Franz, Volz, Theresa Sophie, Richter, Jutta Gisela. 2018. Erythromelalgia. In VASA. Zeitschrift fur Gefasskrankheiten, 47, 91-97. doi:10.1024/0301-1526/a000675. https://pubmed.ncbi.nlm.nih.gov/29299961/

8. Castoro, Ryan, Simmons, Megan, Ravi, Vignesh, Zhou, Lan, Li, Jun. 2018. SCN11A Arg225Cys mutation causes nociceptive pain without detectable peripheral nerve pathology. In Neurology. Genetics, 4, e255. doi:10.1212/NXG.0000000000000255. https://pubmed.ncbi.nlm.nih.gov/30046661/