Among over 300 genodernatoses, causative genes have been identified in 170 monogenetic diseases, while gene mapping has been performed in over 100 monogenetic and polygenctic skin diseases. Researches in genodermatoses has rapidly advanced in China in recent ten years. The causative genes involved in multiple familial trichoepithelioma and primary erythermalgia have been found. Two independent genome-wide scans with DNA markers have been performed to detect genetic linkage related to psoriasis and vitiligo. In this review article, we summarize these most recent findings.
Erythromelalgia ; genetics ; HLA Antigens ; genetics ; Humans ; NAV1.7 Voltage-Gated Sodium Channel ; Proteins ; genetics ; Psoriasis ; genetics ; Sodium Channels ; genetics ; Vitiligo ; genetics

OBJECTIVE: To explore the genetic etiology of a patient with epilepsy and provide genetic counseling. METHODS: A patient who had visited the Center for Reproductive Medicine of Shandong University on November 11, 2020 was selected as the study subject, and her clinic information was collected. Candidate variant was identified through whole exome sequencing (WES), and Sanger sequencing was used for validation. Possible transcriptional changes caused by the variant was detected by reverse transcription-PCR and Sanger sequencing. RESULTS: The patient was a 35-year-old female with no fever at the onset, loss of consciousness and abnormal firing in the temporal lobe, manifesting predominantly as convulsions and fainting. WES revealed that she had harbored a heterozygous c.2841+5G>A variant of the SCN9A gene, which was verified by Sanger sequencing. cDNA sequencing confirmed that 154 bases were inserted between exons 16 and 17 of the SCN9A gene, which probably produced a truncated protein and affected the normal function of the SCN9A protein. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.2841+5G>A variant was classified as likely pathogenic (PVS1_Strong+PM2_Supporting). CONCLUSION The c.2841+5G>A variant of the SCN9A gene probably underlay the epilepsy in this patient. Above finding has enriched the variant spectrum of the SCN9A gene and provided a basis for the prenatal diagnosis and preimplantation genetic testing for this patient.
Humans ; Female ; Pregnancy ; Adult ; Epilepsy/genetics* ; Seizures ; Exons ; DNA, Complementary ; Genetic Counseling ; NAV1.7 Voltage-Gated Sodium Channel

OBJECTIVE: To explore the genetic basis for a child featuring congenital insensitivity to pain (CIP). METHODS: Targeted capture and next generation sequencing (NGS) was carried out for the proband. Suspected pathogenic variants were confirmed by Sanger sequencing of the proband and his parents. RESULTS: The proband was found to harbor compound heterozygous variants of SCN9A gene, namely c.1598delA (p.N533Ifs*31) and c.295_296delCGinsAT (p.R99I), which were respectively inherited from his father and mother. Both variants were predicted to be pathogenic, and neither was reported previously. CONCLUSION The compound heterozygous variants of the SCN9A gene probably underlay the CIP in this child. Above finding has enabled genetic counseling for this family.
Channelopathies ; Child ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; NAV1.7 Voltage-Gated Sodium Channel/genetics* ; Pain Insensitivity, Congenital/genetics*

Objective: To summarize the genetics and clinical phenotypes of epilepsy children with 2q24.3 microdeletion. Methods: All the patients with 2q24.3 microdeletion were retrospectively collected at the Pediatric Department of Peking University First Hospital from March 2017 to July 2022. The features of clinical manifestations, electroencephalogram (EEG), and neuroimaging were analyzed. Results: There were 13 patients with 2q24.3 microdeletion were included. All 13 patients had de novo copy number variation (CNV) with a deletion size ranged 0.18-7.31 Mb. The main pathogenic genes in the region were SCN3A, SCN2A, TTC21B, SCN1A and SCN9A genes. Among the 13 patients, 7 were boys, and 6 were girls. The onset age of epilepsy was 3.3(2.5, 6.0) months. Multiple seizure types were observed, including focal seizures in 13 patients, generalized tonic-clonic seizures (GTCS) in 6 patients, myoclonic seizures in 3 patients, epileptic spasm in 2 patients, and tonic seizures in 2 patients. Seizures were fever sensitivity in 9 patients. Status epilepticus was observed in 6 patients. One case had normal mental motor development and 12 cases had different degrees of developmental delay. Six patients had craniofacial abnormality, 1 had six-finger deformity of the right thumb, and 1 had multiple system abnormalities. EEG showed focal discharge in 3 cases, multifocal discharges in 5 cases, multifocal and generalized discharges in 1 case. Brain magnetic resonance imaging (MRI) showed enlargement of subarachnoid spaces in the frontal and temporal region in 4 patients, enlargement of lateral ventricle in 4 patients and delayed myelination of white matter in 1 patient. Dravet syndrome was diagnosed in 5 cases. The age at the last follow-up were 2.5(1.4,5.5) years, 1 patient was seizure free longer than 1 year, and 12 patients still had seizures. Conclusions: The epilepsy associated with 2q24.3 microdeletion is mainly induced by the deletion of SCN3A, SCN2A and SCN1A genes. The seizure onset age of 2q24.3 microdeletion related epilepsy was in infancy. Multiple seizure types are observed and the common seizure types include focal seizures and GTCS. Most patients have fever sensitivity and status epilepticus. Most patients have developmental delay. The phenotype of patients with deletion of SCN3A and SCN2A gene is more severe than that of patients with deletion of SCN1A gene only.
Humans ; Abnormalities, Multiple ; Chromosomes ; DNA Copy Number Variations ; Epilepsies, Myoclonic ; Epilepsy ; Fever ; NAV1.7 Voltage-Gated Sodium Channel ; Phenotype ; Retrospective Studies ; Seizures ; Status Epilepticus ; Chromosomes, Human, Pair 2

Voltage-gated sodium (Na) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Na channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Na channels, with Na1.1 and Na1.5 each harboring more than 400 mutations. Na channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Na channels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Ca) channel Ca1.1 provides a template for homology-based structural modeling of the evolutionarily related Na channels. In this Resource article, we summarized all the reported disease-related mutations in human Na channels, generated a homologous model of human Na1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Na channels, the analysis presented here serves as the base framework for mechanistic investigation of Na channelopathies and for potential structure-based drug discovery.
Animals ; Calcium Channels, L-Type ; chemistry ; genetics ; metabolism ; Channelopathies ; genetics ; metabolism ; Humans ; Mutation ; NAV1.1 Voltage-Gated Sodium Channel ; chemistry ; genetics ; metabolism ; NAV1.5 Voltage-Gated Sodium Channel ; chemistry ; genetics ; metabolism ; NAV1.7 Voltage-Gated Sodium Channel ; chemistry ; genetics ; metabolism ; Protein Domains ; Rabbits ; Structure-Activity Relationship

The voltage-gated Na channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody (SVmab) reduces Na currents and pain and itch responses in mice. Here, we investigated whether recombinant SVmab (rSVmab) binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltage-sensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7-expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Biotin ; metabolism ; Cells, Cultured ; Disease Models, Animal ; Female ; Ganglia, Spinal ; cytology ; HEK293 Cells ; Humans ; Hybridomas ; chemistry ; Hyperalgesia ; drug therapy ; Male ; Mice ; Mice, Inbred C57BL ; NAV1.5 Voltage-Gated Sodium Channel ; metabolism ; NAV1.7 Voltage-Gated Sodium Channel ; chemistry ; immunology ; metabolism ; Neuralgia ; drug therapy ; metabolism ; Protein Binding ; drug effects ; Recombinant Proteins ; biosynthesis ; therapeutic use ; Sensory Receptor Cells ; drug effects ; physiology

OBJECTIVETo screening mutations of exons 15, 18 and 26 of sodium channel Nav1.7 (SCN9A) gene, and to assess its association with pain related to Parkinsonism.

METHODSRespectively, 101 patients with primary Parkinson's disease (PD) and 104 similar-aged volunteers without PD were recruited from March, 2008 to January, 2011. Mutations of above 3 exons in SCN9A gene was detected with PCR and direct sequencing. For 100 patients with Parkinsonism, the pain was scored with a McGill pain rating scale. Statistical analysis was performed with SPSS.

RESULTSThe prevalence of pain in Parkinsonian was 57%. 43.86% patients with pain were males, and 56.14% were females. Based on Chaudhuri criteria, the pain symptoms may be classified as musculoskeletal pain (10.52%), radicular pain (10.52%), dyskinesis pain (54.38%), pain from akathisia and restlessness (14.04%), dyskinesis combined with radicular pain (5.26%), skeletal muscles pain and headache (1.75%), and arthralgia (3.50%). Two missense mutations were identified, which included 2794A/C (0.941/0.059) (rs12478318) (M932L) in exon 15 and 3448C/T (0.988/0.012) (rs6746030) (R1150W) in exon 18. The wild type A/C for the 2794 locus had a higher prevalence in PD patients with pain, but this was not statistically different. All of the 5 heterozygotes for 3448 (C/T) were found in Parkinsonian patients with pain. No homozygotes were found.

CONCLUSIONThe prevalence of pain was higher in Parkinsonian patients than general population, and the proportion of males to females was similar. More patients have suffered dyskinesis pain. A 3448 (C/T) mutation of SCN9A gene may be related to pathogenesis of pain in Parkinsonism.

Adult ; Aged ; Aged, 80 and over ; Alleles ; Base Sequence ; Exons ; Female ; Gene Frequency ; Genotype ; Humans ; Male ; Middle Aged ; Mutation ; NAV1.7 Voltage-Gated Sodium Channel ; genetics ; Pain ; epidemiology ; etiology ; Parkinson Disease ; complications ; genetics ; Prevalence

PURPOSE: The pathophysiology of discogenic low back pain is not fully understood. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are associated with primary sensory nerve transmission, and the NaV1.7 channel has emerged as an analgesic target. Previously, we found increased NaV1.7 expression in dorsal root ganglion (DRG) neurons innervating injured discs. This study aimed to examine the effect of blocking NaV1.7 on sensory nerves after disc injury. MATERIALS AND METHODS: Rat DRG neurons innervating the L5/6 disc were labeled with Fluoro-Gold (FG) neurotracer. Twenty-four rats underwent intervertebral disc puncture (puncture group) and 12 rats underwent sham surgery (non-puncture group). The injury group was divided into a saline infusion group (puncture+saline group) and a NaV1.7 inhibition group, injected with anti-NaV1.7 antibody (puncture+anti-NaV1.7 group); n=12 per group. Seven and 14 days post-surgery, L1 to L6 DRGs were harvested and immunostained for calcitonin gene-related peptide (CGRP) (an inflammatory pain marker), and the proportion of CGRP-immunoreactive (IR) DRG neurons of all FG-positive neurons was evaluated. RESULTS: The ratio of CGRP-IR DRG neurons to total FG-labeled neurons in the puncture+saline group significantly increased at 7 and 14 days, compared with the non-puncture group, respectively (p<0.05). Application of anti-NaV1.7 into the disc significantly decreased the ratio of CGRP-IR DRG neurons to total FG-labeled neurons after disc puncture at 7 and 14 days (40% and 37%, respectively; p<0.05). CONCLUSION: NaV1.7 antibody suppressed CGRP expression in disc DRG neurons. Anti-NaV1.7 antibody is a potential therapeutic target for pain control in patients with lumbar disc degeneration.
Animals ; Antibodies ; Calcitonin Gene-Related Peptide/metabolism ; Disease Models, Animal ; Ganglia, Spinal/*metabolism ; Intervertebral Disc/*drug effects/*injuries ; Intervertebral Disc Degeneration/metabolism ; Low Back Pain/*physiopathology ; Lumbar Vertebrae/injuries ; Male ; NAV1.7 Voltage-Gated Sodium Channel/*metabolism ; Neurons/*metabolism ; Pain/metabolism ; Rats ; Rats, Sprague-Dawley ; Stilbamidines

Voltage-gated sodium channels (Navs) play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion (hDRG) tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Nav1.7 (~50% of total Nav expression) and lower expression of Nav1.8 (~12%), whereas the mouse DRG has higher expression of Nav1.8 (~45%) and lower expression of Nav1.7 (~18%). To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel (0.1-1 μmol/L) for 24 h. Paclitaxel increased the Nav1.7 but not Nav1.8 expression and also increased the transient Na currents and action potential firing frequency in small-diameter (<50 μm) hDRG neurons. Thus, the hDRG provides a translational model in which to study "human pain in a dish" and test new pain therapeutics.
Action Potentials ; drug effects ; Animals ; Antineoplastic Agents, Phytogenic ; pharmacology ; Dose-Response Relationship, Drug ; Electric Stimulation ; Excitatory Postsynaptic Potentials ; drug effects ; Female ; Ganglia, Spinal ; cytology ; Gene Expression Regulation ; drug effects ; Humans ; In Vitro Techniques ; Male ; Mice ; NAV1.7 Voltage-Gated Sodium Channel ; genetics ; metabolism ; Neurons ; drug effects ; metabolism ; Paclitaxel ; pharmacology ; Patch-Clamp Techniques ; Species Specificity