Scn9a encodes the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons and plays a crucial role in peripheral pain sensation [1,3]. It is essential for nociception in humans, and its function is non-redundant in the pain-sensing pathway [1]. Genetic models, such as gene-edited mice, can be used to study its function and the associated pain-related phenotypes.

In three consanguineous families from northern Pakistan, homozygous nonsense mutations in Scn9a (S459X, I767X and W897X) led to a congenital inability to experience pain, as the mutations caused loss of function of Na(v)1.7 [1]. In a Lebanese family, a novel nonsense, homozygous Scn9a pathogenic variant (SCN9A (NM_001365536.1): c.4633G > T, p.(Glu1545*)) was found in three patients with congenital insensitivity to pain, along with urinary incontinence, and two also had osteoporosis and osteoarthritis [2]. In combat athletes and non-athletes, the SCN9A rs6746030 polymorphism may affect pain perception, with the probability of decreased pain tolerance higher in carriers of certain genotypes [3]. The Scn9a R185H mutant mouse model showed pain hypersensitivity and spontaneous pain, indicating the role of this mutation in patients with small fiber neuropathy having chronic pain [4].

In conclusion, Scn9a is essential for nociception. Studies using gene-edited mouse models and human genetic analyses have revealed its key role in pain-related phenotypes. These findings contribute to understanding pain-related diseases, such as congenital insensitivity to pain and small fiber neuropathy, and may help in the development of novel analgesics targeting Na(v)1.7 [1,4].