Novel SCN9A missense mutations contribute to congenital insensitivity to pain: Unexpected correlation between electrophysiological characterization and clinical phenotype

Abstract

Congenital insensitivity to pain (OMIM 243000) is an extremely rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. Although the SCN9A mutations and phenotypes of painlessness and anosmia/hyposmia in patients are previously well documented, the complex relationship between genotype and phenotype of congenital insensitivity to pain remains unclear. Here, we report a congenital insensitivity to pain patient with novel SCN9A mutations. Functional significance of novel SCN9A mutations was assessed in HEK293 cells expressing Nav1.7, the results showed that p.Arg99His significantly decreased current density and reduced total Nav1.7 protein levels, whereas p.Trp917Gly almost abolished Nav1.7 sodium current without affecting its protein expression. These revealed that mutations in Nav1.7 in this congenital insensitivity to pain patient still retained partial channel function, but the patient showed completely painlessness, the unexpected genotypic-phenotypic relationship of SCN9A mutations in our patient may challenge the previous findings “Nav1.7 total loss-of-function leads to painlessness.” Additionally, these findings are helpful for understanding the critical amino acid for maintaining function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.

Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents

“…We used a BBB score algorithm reported previously (51) to calculate a BBB score of 3 for 194; values of the BBB score in the range of 4 to 6 correctly predict 90% of CNS drugs. However, because 194 reversed (53,54). These two reports support the possibility that even partial inhibition of NaV1.7 leads to painlessness.…”

“…Although the high degree (>90%) of channel block/current (in vitro) has been proposed as a prerequisite for achieving analgesia (in vivo), to our knowledge, no study has proven target engagement and the extent of block in vivo. However, evidence from human genetic studies shows that despite having congenital insensitivity to pain (CIP) due to mutations in NaV1.7, partial channel function was still retained in patients ( 53 , 54 ). These two reports support the possibility that even partial inhibition of NaV1.7 leads to painlessness.…”

Phenotype-driven identification of drug targets for post-COVID-19 anosmia

“…Further support for this hypothesis comes from studies showing that humans with a loss of function (LoF) mutation in SCN9A have an insensitivity to pain 13 , while gain of function (GoF) mutations have been associated with pain disorders 14 . LoF mutation in SCN9A in mice was shown to give rise to anosmia due to electrical signals failing to transmit through the first synapse of the olfactory nerve 14 , and specifically due to inhibition of neurotransmitter function 12 .…”

Nav1.7 gain-of-function mutation I228M triggers age-dependent nociceptive insensitivity and C-LTMR dysregulation

“…These channels are distributed across several different subtypes of DRGs and contribute to electrogenesis, with Na v 1.7 and Na v 1.9 contributing to the action potential threshold and Na v 1.8 the action potential upstroke ( Rush et al, 2007 ). Gain-of-function (GOF), single nucleotide mutations in Na v 1.7 are specifically implicated in a range of painful conditions including: inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD) ( Dib-Hajj et al, 2013 ; Drenth and Waxman, 2007 ), and small fiber neuropathy (SFN) ( Faber et al, 2012 ; Hoeijmakers et al, 2012 ; Huang et al, 2014 ), while recessive loss-of-function (LOF) mutations primarily result in congenital insensitivity to pain (CIP) ( Cox et al, 2006 ; Sun et al, 2020 ). Canonically, pain in these conditions is directly associated with heterozygous GOF mutations with an increase in sodium conductance and neuronal hyperexcitability, whereas a lack of pain is associated with homozygous LOF, largely due to nonsense mutations, that cause DRG neuron hypoexcitability.…”