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

Abstract

Congenital insensitivity to pain (CIP) comprises the rare heritable disorders without peripheral neuropathy that feature inability to feel pain. Fracturing and joint destruction are common complications, but lack detailed studies of mineral and skeletal homeostasis and bone histology. In 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic diarrhea, and hyperhidrosis. Here, we studied a mother and two children with CIP by physical examination, biochemical testing, radiological imaging including DXA, iliac crest histology, and mutation analysis. She suffered fractures primarily of her lower extremities beginning at age two years, and had Charcot deformity of both ankles and joint hypermobility. Nerve conduction velocity and biopsy and electromyography were normal. Her children had recurrent major fractures beginning in early childhood, joint hypermobility, and chronic diarrhea. She had an excoriated external nare, and both children had hypertrophic scars from scratching. Skin collagen studies were normal. Radiographs revealed fractures and deformities. However, lumbar spine and total hip BMD Z-scores, biochemical parameters of mineral and skeletal homeostasis, and iliac crest histology of the mother (after in vivo tetracycline labeling) were normal. Genomic DNA from the children revealed a unique heterozygous missense mutation in exon 23 (c.3904C>T, p.Leu1302Phe) of SCN11A that is absent in SNP databases and alters an evolutionarily conserved amino acid. This autosomal dominant CIP reflects the second gain-of-function mutation of SCN11A. Perhaps joint hypermobility is an unreported feature. How mutation of Nav1.9 causes fracturing remains unexplained. Lack of injury awareness is typically offered as the reason, and was supported by our unremarkable biochemical, radiological, and histological findings indicating no skeletal pathobiology. However, low-trauma fracturing in these patients suggests an uncharacterized defect in bone quality.

Pain insensitivity: distal S6-segment mutations in NaV1.9 emerge as critical hotspot

“…b Membrane topology (top) of Na V 1.9 with the position of alteration p.L396P at the distal end of transmembrane segment 6 in domain I highlighted in red. Notably, p.L396P is located at the intracellular mouth of the channel pore (bottom view), a region harboring also the two other CIP-associated alterations previously reported (p.L811P [3], blue; p.L1302F [4], black). c Representative current traces of human wild-type Na V 1.9 (black) and p.L396P (red) mutant channels obtained from murine SCN11A −/− DRG neurons transiently transfected with the corresponding expression constructs as described earlier [5].…”

“…Alteration of p.L396P is located at the distal end of S6 in DI. Together with the pain insensitivity mutation p.L811P in Na V 1.9 [3], and the recently reported yet functionally uncharacterized p.L1302F mutation [4], it is becoming apparent that gain-of-function mutations in the distal S6-segments of the ion channel, close to the channel gate, do not promote painful episodes but impair pain perception (Fig. 1b).…”

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

“…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. The expression of Na v 1.9 in nociceptors and myenteric neurons is consistent with the symptoms of distal extremity pain and gastrointestinal disturbances reported by patients carrying Na v 1.9 mutations 12 14 16–18…”

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

“…Targeted sequence analysis of Na V 1.7, Na V 1.8, and Na V 1.9 in the proband identified a heterozygous Na V 1.9 coding variant (c.3904C>T, p.Leu1302Phe [L1302F]) ( Figure 1B), which was recently reported in an unrelated family with insensitivity to pain (32). The variant affects a highly conserved residue in the S6 segment of domain III and is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/).…”

“…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.…”