Understanding the genetic basis of congenital insensitivity to pain

Drissi, Ichrak; Woods, William A.

doi:10.1093/bmb/ldaa003

Cited by 42 publications

(49 citation statements)

References 54 publications

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“…Even though the exact neuronal basis for human chronic pain is unknown, insights have been obtained through the identification of genes causing congenital insensitivity to pain 22 , 60 . While most of the genes causing painless phenotype are abundantly expressed in all DRG neuron types, some display restricted expression patterns, thus opening for linking neuronal types to phenotype.…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain

et al. 2021

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Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

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Section: Discussionmentioning

confidence: 99%

Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain

et al. 2021

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show abstract

“…Even though the exact neuronal basis for human chronic pain is unknown, insights have been obtained through the identification of genes causing congenital insensitivity to pain 22,60 . While most of the genes causing painless phenotype are abundantly expressed in all DRG neuron types, some display restricted expression patterns, thus opening for linking neuronal types to phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…While most of the genes causing painless phenotype are abundantly expressed in all DRG neuron types, some display restricted expression patterns, thus opening for linking neuronal types to phenotype. These includes congenital insensitivity to pain by mutations in SCN9A (Nav1.7), SCN11A (Nav1.9) and NTRK1 (TRKA) [21][22][23][24][25]61 and PRDM12 62 . In contrast to mouse which display an enriched expression in nociceptors, macaque SCN9A is broadly expressed at similar levels in all neuronal types, while SCN11A expression is more similar to mouse with expression at varying levels in all unmyelinated neuronal types (C-LTMRs, PEP1, NP1-3,) with very low levels in TRPM8 high , myelinated nociceptors and A-LTMRs (see https://ernforsgroup.shinyapps.io/macaquedrg/ for interrogation of gene expression).…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptomics of primate sensory neurons identifies cell types associated with human chronic pain

Kupari

Usoskin

Lou

et al. 2020

Preprint

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Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of human chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.

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“…Complete insensitivity to pain is characterised by loss of all pain sensations throughout patient's life. SCN9A loss of function mutations cause an autosomal recessive CIP [19,34]. Several mutations have been identified, and most are nonsense mutations causing truncated proteins, Table 5.…”

Section: Complete Insensitivity To Painmentioning

confidence: 99%

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

Baker

Nassar

2020

Pflugers Arch - Eur J Physiol

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Chronic pain is a global problem affecting up to 20% of the world's population and has a significant economic, social and personal cost to society. Sensory neurons of the dorsal root ganglia (DRG) detect noxious stimuli and transmit this sensory information to regions of the central nervous system (CNS) where activity is perceived as pain. DRG neurons express multiple voltage-gated sodium channels that underlie their excitability. Research over the last 20 years has provided valuable insights into the critical roles that two channels, Na V 1.7 and Na V 1.9, play in pain signalling in man. Gain of function mutations in Na V 1.7 cause painful conditions while loss of function mutations cause complete insensitivity to pain. Only gain of function mutations have been reported for Na V 1.9. However, while most Na V 1.9 mutations lead to painful conditions, a few are reported to cause insensitivity to pain. The critical roles these channels play in pain along with their low expression in the CNS and heart muscle suggest they are valid targets for novel analgesic drugs. Keywords Pain. Dorsal root ganglia. Human mutations. Painful conditions. Voltage-gated sodium channels. Na v 1.

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Understanding the genetic basis of congenital insensitivity to pain

Cited by 42 publications

References 54 publications

Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain

Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain

Single cell transcriptomics of primate sensory neurons identifies cell types associated with human chronic pain

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

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