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 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 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

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

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

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