Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SCN9A, the gene which encodes voltage-gated sodium channel Na(v)1.7, is located on human chromosome 2 within a cluster of other members of this gene family. Na(v)1.7 is present at high levels in most peripheral nociceptive neurons in dorsal root ganglion (DRG) and in sympathetic neurons. In addition to its focal tissue-specific expression, Na(v)1.7 is distinguished by its ability to amplify small depolarizations, thus acting as a threshold channel and modulating excitability. Dominantly inherited gain-of-function mutations in SCN9A have been linked to two familial painful disorders: inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). One set of mutations leads to severe episodes of pain in the feet and hands in patients with IEM, and a different set of mutations causes pain in a perirectal, periocular, and mandibular distribution in patients with PEPD. These mutations allow mutant channels to activate in response to weaker stimuli, or to remain open longer in response to stimulation. The introduction of mutant channels into DRG neurons alters electrogenesis and renders these primary sensory neurons hyperexcitable. Mutant Na(v)1.7 channels lower the threshold for single action potentials and increase the number of action potentials that neurons fire in response to suprathreshold stimuli. In contrast, recessively inherited loss-of-function mutations in SCN9A, which cause a loss of function of Na(v)1.7 in patients, lead to indifference to pain with sparing of motor and cognitive abilities. The central role of Na(v)1.7 in these disorders, and the apparently limited consequences of loss of this channel in humans make it an attractive target for treatment of pain.
 ...
PMID:Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes. 1918 86

The sensation of pain is important and there may be serious consequences if it is missing. Recently, the genetic basis for a channelopathy characterised by a congenital inability to experience pain has been described and channelopathy-associated insensitivity to pain has been proposed as a suitable name for this condition. Different mutations in the SCN9A gene causing loss of function of the voltage-gated sodium channel Nav1.7 have been reported in patients with this rare disease. Here we describe a woman with insensitivity to pain with two novel mutations in the SCN9A gene, coding for the Nav1.7 channel. We also discuss the finding of anosmia which apparently is a common feature in these patients.
Pain 2009 May
PMID:Two novel SCN9A mutations causing insensitivity to pain. 1930 93

Primary erythermalgia (erythromelalgia) is a rare autosomal dominant condition characterized by intermittent attacks of erythema, increased skin temperature and severe burning pain in the extremities, in a bilateral symmetrical distribution. Mutations in the SCN9A gene, which encodes a voltage-gated sodium channel have been shown to cause this disease. We report a family identified to have a mutation in the SCN9A gene, in which one severely affected family member has responded to the therapeutic combination of gabapentin and carbamazepine treatment.
 ...
PMID:Treatment with carbamazepine and gabapentin of a patient with primary erythermalgia (erythromelalgia) identified to have a mutation in the SCN9A gene, encoding a voltage-gated sodium channel. 1954 32

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 low-threshold 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.
 ...
PMID:Developments in autonomic research: a review of the latest literature. 1959 30

Congenital absence of pain perception is a rare phenotype. Here we report two unrelated adult individuals who have a previously unreported neuropathy consisting of congenital absence of pain with hyperhidrosis (CAPH). Both subjects had normal intelligence and productive lives despite failure to experience pain due to broken bones, severe cold or burns. Functional assessments revealed that both are generally hypesthetic with thresholds greater than two standard deviations above normal for a several of modalities in addition to noxious stimuli. Sweating was 3 to 8-fold greater than normal. Sural nerve biopsy showed that all types of myelinated and unmyelinated fibers were severely reduced. Extensive multi-antibody immunofluorescence analyses were conducted on several skin biopsies from the hands and back of one CAPH subject and two normal subjects. The CAPH subject had all normal types of immunochemically and morphologically distinct sensory and autonomic innervation to the vasculature and sweat glands, including a previously unknown cholinergic arterial innervation. Virtually all other types of normal cutaneous C, Adelta and Abeta-fiber endings were absent. This subject had no mutations in the genes SCN9A, SCN10A, SCN11A, NGFB, TRKA, NRTN and GFRA2. Our findings suggest three hypotheses: (1) that development or maintenance of sensory innervation to cutaneous vasculature and sweat glands may be under separate genetic control from that of all other cutaneous sensory innervation, (2) the latter innervation is preferentially vulnerable to some environmental factor, and (3) vascular and sweat gland afferents may contribute to conscious cutaneous perception.
Pain 2009 Dec 15
PMID:Absence of pain with hyperhidrosis: a new syndrome where vascular afferents may mediate cutaneous sensation. 2082 34

Sodium channel Na(V)1.7, encoded by the SCN9A gene, is preferentially expressed in nociceptive primary sensory neurons, where it amplifies small depolarizations. In studies on a family with inherited erythromelalgia associated with Na(V)1.7 gain-of-function mutation A863P, we identified a nonsynonymous single-nucleotide polymorphism within SCN9A in the affected proband and several unaffected family members; this polymorphism (c. 3448C&T, Single Nucleotide Polymorphisms database rs6746030, which produces the amino acid substitution R1150W in human Na(V)1.7 [hNa(V)1.7]) is present in 1.1 to 12.7% of control chromosomes, depending on ethnicity. In this study, we examined the effect of the R1150W substitution on function of the hNa(V)1.7 channel, and on the firing of dorsal root ganglion (DRG) neurons in which this channel is normally expressed. We show that this polymorphism depolarizes activation (7.9-11mV in different assays). Current-clamp analysis shows that the 1150W allele depolarizes (6mV) resting membrane potential and increases ( approximately 2-fold) the firing frequency in response to depolarization in DRG neurons in which it is present. Our results suggest that polymorphisms in the Na(V)1.7 channel may influence susceptibility to pain.
 ...
PMID:A sodium channel gene SCN9A polymorphism that increases nociceptor excitability. 2003 88

Chronic pain often represents a severe, debilitating condition. Up to 10% of the worldwide population are affected, and many patients are poorly responsive to current treatment strategies. Nociceptors detect noxious conditions to produce the sensation of pain, and this signal is conveyed to the CNS by means of action potentials. The fast upstroke of action potentials is mediated by voltage-gated sodium channels, of which nine pore-forming alpha-subunits (Nav1.1-1.9) have been identified. Heterogeneous functional properties and distinct expression patterns denote specialized functions of each subunit. The Nav1.7 and Nav1.8 subunits have emerged as key molecules involved in peripheral pain processing and in the development of an increased pain sensitivity associated with inflammation and tissue injury. Several mutations in the SCN9A gene encoding for Nav1.7 have been identified as important cellular substrates for different heritable pain syndromes. This review aims to cover recent progress on our understanding of how biophysical properties of mutant Nav1.7 translate into an aberrant electrogenesis of nociceptors. We also recapitulate the role of Nav1.8 for peripheral pain processing and of additional sodium channelopathies which have been linked to disorders with pain as a significant component.
 ...
PMID:Sodium channelopathies and pain. 2010 9

The gene SCN9A is responsible for three human pain disorders. Nonsense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped 27 SCN9A SNPs in 578 individuals with a radiographic diagnosis of osteoarthritis and a pain score assessment. A significant association was found between pain score and SNP rs6746030; the rarer A allele was associated with increased pain scores compared to the commoner G allele (P = 0.016). This SNP was then further genotyped in 195 pain-assessed people with sciatica, 100 amputees with phantom pain, 179 individuals after lumbar discectomy, and 205 individuals with pancreatitis. The combined P value for increased A allele pain was 0.0001 in the five cohorts tested (1277 people in total). The two alleles of the SNP rs6746030 alter the coding sequence of the sodium channel Nav1.7. Each was separately transfected into HEK293 cells and electrophysiologically assessed by patch-clamping. The two alleles showed a difference in the voltage-dependent slow inactivation (P = 0.042) where the A allele would be predicted to increase Nav1.7 activity. Finally, we genotyped 186 healthy females characterized by their responses to a diverse set of noxious stimuli. The A allele of rs6746030 was associated with an altered pain threshold and the effect mediated through C-fiber activation. We conclude that individuals experience differing amounts of pain, per nociceptive stimulus, on the basis of their SCN9A rs6746030 genotype.
 ...
PMID:Pain perception is altered by a nucleotide polymorphism in SCN9A. 2021 37

Because ion channel function is a fundamental element of any nociceptive signalling, it is not surprising that numerous channelopathies have recently emerged as likely causes of several inherited clinical pain conditions. For example, numerous missense mutations in the Na(v)1.7 gene SCN9A have recently been linked to a congenital inability to sense pain. Establishing the link between a clinical pain phenotype to an inherited molecular dysfunction of a specific protein has its challenges and requires the collaboration between many specialists. However, once established, such a linkage offers the promise of a powerful and elegant way to mechanistically explain the aspects of the disease studied.
 ...
PMID:Linkage analysis and functional evaluation of inherited clinical pain conditions. 2033 31

Voltage-gated sodium channelopathies underlie many excitability disorders. Genes SCN1A, SCN2A and SCN9A, which encode pore-forming alpha-subunits Na(V)1.1, Na(V)1.2 and Na(V)1.7, are clustered on human chromosome 2, and mutations in these genes have been shown to underlie epilepsy, migraine, and somatic pain disorders. SCN3A, the gene which encodes Na(V)1.3, is part of this cluster, but until recently was not associated with any mutation. A charge-neutralizing mutation, K345Q, in the Na(V)1.3 DI/S5-6 linker has recently been identified in a patient with cryptogenic partial epilepsy. Pathogenicity of the Na(V)1.3/K354Q mutation has been inferred from the conservation of this residue in all sodium channels and its absence from control alleles, but functional analysis has been limited to the corresponding substitution in the cardiac muscle sodium channel Na(V)1.5. Since identical mutations may produce different effects within different sodium channel isoforms, we assessed the K354Q mutation within its native Na(V)1.3 channel and studied the effect of the mutant Na(V)1.3/K354Q channels on hippocampal neuron excitability. We show here that the K354Q mutation enhances the persistent and ramp currents of Na(V)1.3, reduces current threshold and produces spontaneous firing and paroxysmal depolarizing shift-like complexes in hippocampal neurons. Our data provide a pathophysiological basis for the pathogenicity of the first epilepsy-linked mutation within Na(V)1.3 channels and hippocampal neurons.
 ...
PMID:A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons. 2070 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>