Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders

Drenth, Joost P.H.; Waxman, Stephen G.

doi:10.1172/jci33297

Cited by 304 publications

(277 citation statements)

References 53 publications

(74 reference statements)

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“…Recent genetic studies have identified Nav1.7 dysfunction in three different human pain disorders -i.e. primary erythermalgia, paroxysmal extreme pain disorder and channelopathy-associated insensitivity to pain or congenital 'indifference' to pain 22 -not necessarily featuring loss of pain sensitivity, but expressing more kinds of pain disorders. Depending on the function, Nav1.7 mutations can be divided in 'gain-of-function' mutations, causing primary erythermalgia and paroxysmal extreme pain disorder, and 'loss-of-function' Nav1.7 mutants which lead to congenital 'indifference' to pain.…”

Section: Discussionmentioning

confidence: 99%

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report

Cascella

Muzio

2017

Rev. chil. pediatr.

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Introduction. Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. Case report. A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. Conclusions. This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.

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Section: Discussionmentioning

confidence: 99%

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report

Cascella

Muzio

2017

Rev. chil. pediatr.

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“…Consistent with this scenario, mice lacking the SCN9A gene through specific deletion in nociceptive sensory neurons exhibited reduced responses to inflammatory, mechanical, and thermal pain (25). Furthermore, mutations of the SCN9A gene that cause excessive channel activities revealed the inherited pain syndrome erythermalgia and paroxysmal extreme pain disorder (26). Despite the potential therapeutic importance of Nav1.7 as a pain modulator, the major factors, which regulate the expression of SCN9A, have not been identified.…”

Section: Endritic Cells (Dc) Act As Conductors Of the Immune Systemmentioning

confidence: 99%

Voltage-Gated Sodium Channel Nav1.7 Maintains the Membrane Potential and Regulates the Activation and Chemokine-Induced Migration of a Monocyte-Derived Dendritic Cell Subset

Kis-Tóth

Hajdú

Bacskai

et al. 2011

The Journal of Immunology

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Expression of CD1a protein defines a human dendritic cell (DC) subset with unique functional activities. We aimed to study the expression of the Nav1.7 sodium channel and the functional consequences of its activity in CD1a− and CD1a+ DC. Single-cell electrophysiology (patch-clamp) and quantitative PCR experiments performed on sorted CD1a− and CD1a+ immature DC (IDC) showed that the frequency of cells expressing Na+ current, current density, and the relative expression of the SCN9A gene encoding Nav1.7 were significantly higher in CD1a+ cells than in their CD1a− counterparts. The activity of Nav1.7 results in a depolarized resting membrane potential (−8.7 ± 1.5 mV) in CD1a+ IDC as compared with CD1a− cells lacking Nav1.7 (−47 ± 6.2 mV). Stimulation of DC by inflammatory signals or by increased intracellular Ca2+ levels resulted in reduced Nav1.7 expression. Silencing of the SCN9A gene shifted the membrane potential to a hyperpolarizing direction in CD1a+ IDC, resulting in decreased cell migration, whereas pharmacological inhibition of Nav1.7 by tetrodotoxin sensitized the cells for activation signals. Fine-tuning of IDC functions by a voltage-gated sodium channel emerges as a new regulatory mechanism modulating the migration and cytokine responses of these DC subsets.

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“…Finally, Nilsen and colleagues, from the Department of Neuroscience at the Norwegian University of Science and Technology in Trondheim, Norway, report in the May 2009 issue of Pain a woman with insensitivity to pain in whom two novel mutations in the SCN9A gene, which codes for a specific subunit of the voltage-gated sodium channel Na(v)1.7, were found [10]. Indeed, as described by Drenth and Waxman, of the Department of Medicine at the University Medical Center St. Radboud in Nijmegen, The Netherlands, in the December 2007 issue of the Journal of Clinical Investigation, disorders in the SCN9A gene have important consequences for the processing of nociceptive information: while nonsense mutations in Na(v)1.7 result in insensitivity to pain, gain-of-function missense mutations in Na(v) 1.7 have been shown to cause paroxysmal extreme pain disorder [6].…”

Section: Genetic Clustersmentioning

confidence: 99%

Developments in autonomic research: a review of the latest literature

Macefield

2009

Clin Auton Res

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Small-diameter afferents do not just subserve pain and temperature sensibilities, important for protection of the body though they are: there is a system of lowthreshold unmyelinated afferents that respond to light stroking (C-tactile afferents) and they are believed to subserve the affective components of touch. Patients with large-fibre sensory neuropathies exhibit skin sympathetic responses to stroking, and report the stimuli as feeling pleasant. Moreover, the posterior insula is activated. Patients with small-diameter sensory neuropathies, specifically those with congenital insensitivity to pain, suffer from cumulative injuries that can lead to joint degeneration. There is evidence that the nociceptive (and sympathetic) axons die because nerve growth factor is not being produced by the target tissues; patients with congenital insensitivity to pain have mutations in the NTRK1 gene, the gene responsible for producing the TrkA receptor, but there is also evidence for mutations in the SCN9A gene, which codes for a specific subunit of the voltage-gated sodium channel. Specific mutations, leading to clusters of cases of congenital insensitivity to pain, have been found in several geographical locations, with several genetic mutations having been documented. Interestingly, even patients with congenital insensitivity to pain, despite having never experienced pain, can still empathise with the pain in others-we do not need to feel pain in order to empathise, but we do need to feel pain in order to ensure that our body looks after itself.

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Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders

Cited by 304 publications

References 53 publications

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report

Voltage-Gated Sodium Channel Nav1.7 Maintains the Membrane Potential and Regulates the Activation and Chemokine-Induced Migration of a Monocyte-Derived Dendritic Cell Subset

Developments in autonomic research: a review of the latest literature

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