Human loss or gain-of-function mutations in the gene encoding Na<sub>v</sub>1.7 channels (SCN9A) are associated with either absence of pain, as reported for congenital insensitivity to pain, or with exacerbation of pain, as reported for primary erythromelalgia and paroxysmal extreme pain disorder.
Genetic studies in families demonstrating recessively inherited channelopathy-associated insensitivity to pain have identified nonsense mutations that result in truncation of the voltage-gated sodium channel type IX subunit (SCN9A), a 113.5-kb gene comprising coding 26 exons.
For example, the voltage-gated sodium ion channel Nav1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Nav1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy.
This study aimed to explore the role of a nonsynonymous single-nucleotide polymorphism, 3312G>T, in SCN9A, which was identified in probands with congenital indifference to pain, but which is also present in normal controls, in the prediction of individual baseline pain perception, and postoperative pain sensitivity in the general population.
Mutations in SCN9A, encoding the alpha subunit of the voltage-gated sodium channel (Nav1.7), have caused severe pain disorders and congenital insensitivity to pain.
From human genetics, a small number of patients with mutations in the genes encoding nerve growth factor/TrkA signaling and in a particular sodium channel subunit (SCN9a, encoding Nav1.7) show congenital analgesia with limited other effects.
A direct role of sodium channels in pain has recently been confirmed by establishing a monogenic link between SCN9A, the gene which encodes sodium channel Nav1.7, and pain disorders in humans, with gain-of-function mutations causing severe pain syndromes, and loss-of-function mutations causing congenital indifference to pain.
A direct role of sodium channels in pain has recently been confirmed by establishing a monogenic link between SCN9A, the gene which encodes sodium channel Nav1.7, and pain disorders in humans, with gain-of-function mutations causing severe pain syndromes, and loss-of-function mutations causing congenital indifference to pain.
Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE).