ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 62 citations in OpenAlex.
- Deciphering the Structural and Functional Effects of the R1150W Non-Synonymous Variant in SCN9A Linked to Altered Pain Perception.NeuroSci · 2025Article
- Comprehensive Proteomic Profiling of Human Nav1.7-Interacting Proteins Reveals Conserved Regulatory Networks Involved in Nociceptive Signaling.Neuroscience insights · 2025Article
- Small fibre neuropathy in Fabry disease: a human-derived neuronalBrain communications · 2024Article
- Novel SCN9A variant associated with congenital insensitivity to pain.Molecular biology reports · 2023Article
- Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents.Science translational medicine · 2021Article
- Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort.Journal of the neurological sciences · 2021Article
- The physiological function of different voltage-gated sodium channels in pain.Nature reviews. Neuroscience · 2021Review
- Hydropathicity-based prediction of pain-causing NaV1.7 variants.BMC bioinformatics · 2021Article
- Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes.eLife · 2021Article
- The development of somatosensory neurons: Insights into pain and itch.Current topics in developmental biology · 2021Review
- FGF13 Is Required for Histamine-Induced Itch Sensation by Interaction with NaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Uncoupling sodium channel dimers restores the phenotype of a pain-linked NaBritish journal of pharmacology · 2020Article
- Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels.Pflugers Archiv : European journal of physiology · 2020Review
- Comprehensive engineering of the tarantula venom peptide huwentoxin-IV to inhibit the human voltage-gated sodium channel hNaThe Journal of biological chemistry · 2020Article
- Vitamin D and Its Potential Interplay With Pain Signaling Pathways.Frontiers in immunology · 2020Review
- Article
- Defining the Functional Role of NaNeuron · 2019Article
- Advances in understanding nociception and neuropathic pain.Journal of neurology · 2018Review
- Pharmacological characterisation of the highly NaScientific reports · 2017Article
- Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief.Expert opinion on therapeutic targets · 2016Review
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.
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