The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P

Congenital insensitivity to pain: Fracturing without apparent skeletal pathobiology caused by an autosomal dominant, second mutation in SCN11A encoding voltage-gated sodium channel 1.9

“…They also manifested muscle weakness, delayed motor development, failure-to-thrive, hyperhidrosis, and chronic diarrhea. (24) The following year, a Scottish girl with sporadic CIP and the same clinical phenotype was reported by Woods et al (25) to have the identical mutation (c.2432T>C, p.Leu811Pro) in SCN11A .…”

“…However, only three people with CIP from SCN11A mutation have been reported -- all had sporadic disease from the identical heterozygous mutation in exon 15 (c.2432T>C, p.Leu811Pro) located at the distal end of segment 6 in domain II (S6, DII) (Figure 6E, F). (24,25,38) In the mature transmembrane Na v 1.9 protein, the altered amino acid lies immediately adjacent to the channel's pore (Figure 6F). In knock-in mice, this mutant Na v 1.9 caused severe cutaneous lesions at the cervical area, and reduced pain sensitivity without morphologic changes in sensory axons or small nerve fibers in the skin.…”

Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability

“…Other family members, including the unaffected maternal grandmother and 2 unaffected maternal aunts, did not harbor the L1302F variant. We either loss of pain perception (26,31,32) or the opposite phenotypes of familial episodic pain and painful peripheral neuropathy (33)(34)(35)(36)(37). All mutant Na V 1.9 channels for which biophysical data are available show hyperpolarizing shifts in channel activation, which is consistent with a gain of function at the channel level, despite the contrasting nature of the associated clinical phenotypes.…”

“…By contrast, dominant Na V 1.7 mutations that produce gain-of-function changes, including a hyperpolarizing shift in the voltage dependence of activation at the channel level, are associated with genetic disorders featuring increased pain sensation (49)(50)(51)(52). Unlike the distinct relationships between channel defects and clinical phenotypes for Na V 1.7, dominant mutations that produce gain of function in Na V 1.9 at the channel level have been associated with syndromes characterized by both insensitivity to pain (26,31) and severe pain (6,33,34,36). The mechanistic link between Na V 1.9 gain of function and insensitivity to pain has been elusive.…”

Familial gain-of-function Nav1.9 mutation in a painful channelopathy

“…Sporadic mutations of Na v 1.9 have been identified in patients with painful small-fibre neuropathy 14 15. Paradoxically, one gain-of-function mutation in Na v 1.9 has been reported in patients with congenital insensitivity to pain (CIP), albeit without a clear mechanistic basis for the reduced excitability of sensory neurons 16 17. An additional Na v 1.9 mutation has been reported in a case of familial CIP associated with chronic diarrhoea;18 however, functional analysis of this mutation was not reported.…”