Pancreatitis Pathology and Treatment (3)
Liver Disease Diagnosis and Treatment (2)
Pancreatic function and diabetes (2)
Pain Mechanisms and Treatments (1)
Ion channel regulation and function (1)
Cheng X, Dib-Hajj SD, Tyrrell L, Te Morsche RH, Drenth JP , et al.
Brain : a journal of neurology •
Gain-of-function missense mutations of voltage-gated sodium channel Na(V)1.7 have been linked to the painful disorder inherited erythromelalgia. These mutations hyperpolarize activation, slow deactivation and enhance currents evoked by slow ramp stimuli (ramp currents). A correlation has recently been suggested between the age of onset of inherited erythromelalgia and the extent of hyperpolarizing shifts in mutant Na(V)1.7 channel activation; mutations causing large activation shifts have been linked to early age of onset inherited erythromelalgia, while mutations causing small activation shifts have been linked to age of onset within the second decade of life. Here, we report a family with inherited erythromelalgia with an in-frame deletion of a single residue--leucine 955 (Del-L955) in DII/S6. The proband did not show symptoms until the age of 15 years, and her affected mother only experienced mild symptoms during adolescence, which disappeared at the age of 38 years. Del-L955 shows no effect on Na(V)1.7 current density and fast inactivation, but causes an approximately -24 mV shift in activation, together with increases in amplitude of persistent currents and ramp currents. The mutation also produces an approximately -40 mV shift in slow inactivation, which reduces channel availability. Comparison of the effects of the Del-L955 mutation on dorsal root ganglion neuron hyperexcitability with those produced by another inherited erythromelalgia mutation (L858F) that does not enhance slow inactivation suggests that a delayed age of onset and milder symptoms in association with a large shift of channel activation, enhanced persistent and enhanced ramp currents may be related to the approximately -40 mV shift in slow inactivation for Del-L955, the largest shift thus far demonstrated in mutant Na(V)1.7 channels. Our results suggest that despite the pivotal role of activation shift in inherited erythromelalgia development, slow inactivation may regulate clinical phenotype by altering channel availability.
Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV , et al.
Proceedings of the National Academy of Sciences of the United States of America •
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.
Choi JS, Cheng X, Foster E, Leffler A, Tyrrell L , et al.
Brain : a journal of neurology •
The Na(v)1.7 sodium channel is preferentially expressed in nocioceptive dorsal root ganglion and sympathetic ganglion neurons. Gain-of-function mutations in Na(v)1.7 produce the nocioceptor hyperexcitability underlying inherited erythromelalgia, characterized in most kindreds by early-age onset of severe pain. Here we describe a mutation (Na(v)1.7-G616R) in a pedigree with adult-onset of pain in some family members. The mutation shifts the voltage-dependence of channel fast-inactivation in a depolarizing direction in the adult-long, but not in the neonatal-short splicing isoform of Na(v)1.7 in dorsal root ganglion neurons. Altered inactivation does not depend on the age of the dorsal root ganglion neurons in which the mutant is expressed. Expression of the mutant adult-long, but not the mutant neonatal-short, isoform of Na(v)1.7 renders dorsal root ganglion neurons hyperexcitable, reducing the current threshold for generation of action potentials, increasing spontaneous activity and increasing the frequency of firing in response to graded suprathreshold stimuli. This study shows that a change in relative expression of splice isoforms can contribute to time-dependent manifestation of the functional phenotype of a sodium channelopathy.
Estacion M, Dib-Hajj SD, Benke PJ, Te Morsche RH, Eastman EM , et al.
The Journal of neuroscience : the official journal of the Society for Neuroscience •
Gain-of-function mutations of Na(V)1.7 have been shown to produce two distinct disorders: Na(V)1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; Na(V)1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel Na(V)1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4-S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (-7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in Na(V)1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a Na(V)1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.
To elucidate the rate of missense mutations in the SCN9A gene (which encodes sodium channel Na(v)1.7) (OMIM 603415) among patients with primary erythermalgia and to examine the possibility that other sodium channels can cause the disease. Case series. Department of Medicine, Radboud University Nijmegen, the Netherlands. Six patients with sporadic and 9 with unique familial primary erythermalgia. Interventions Questionnaire to determine clinical profile and sequencing of all coding exons from SCN9A and those of SCN10A (OMIM 604427) and SCN11A (OMIM 604385) in 2 selected cases with a clear family history of the disease. Detection of SCN9A mutation. We identified 1 patient with an SCN9A mutation. This mutation (I848T) has been associated with primary erythermalgia. Sequencing of 2 other candidate genes did not show mutations in 2 patients with familial primary erythermalgia. The Na(v)1.7 voltage-gated sodium channels are related to syndromes of altered nociception. We detected a low SCN9A mutation rate in patients with primary erythermalgia, suggesting that pain syndromes in the skin may have a polygenic basis.
Primary erythermalgia is a rare disorder characterized by recurrent attacks of red, warm and painful hands and/or feet. In a previous study we reported localization of a gene for primary erythermalgia to a 7.94-cM region on chromosome 2q. A recent study reported voltage-gated sodium channel gene SCN9a sequence variants in a family and a single individual with primary erythermalgia. To describe the clinical characteristics of a large three-generation family with primary erythermalgia and to test for genetic linkage to chromosome 2q. We collected clinical data of a 10-member three-generation family with autosomal dominant primary erythermalgia. In addition, we performed linkage analysis and searched for SCN9a variants using a restriction fragment length polymorphism assay. We established the diagnosis of autosomal dominant primary erythermalgia in six of 10 family members. We excluded linkage to chromosome 2q and could not detect SCN9A variants in this family. In this family with autosomal dominant primary erythermalgia, exclusion of linkage to chromosome 2q is strongly suggestive for genetic heterogeneity.