Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The voltage-gated sodium channel SCN8A is associated with inherited neurological disorders in the mouse that include ataxia, dystonia, severe muscle weakness, and paralysis. We report the complete coding sequence and exon organization of the human SCN8A gene. The predicted 1980 amino acid residues are distributed among 28 exons, including two pairs of alternatively spliced exons. The SCN8A protein is evolutionarily conserved, with 98.5% amino acid sequence identity between human and mouse. Consensus sites for phosphorylation of serine/threonine and tyrosine residues are present in cyoplasmic loop domains. The polymorphic (CA)n microsatellite marker D12S2211, with PIC = 0.68, was isolated from intron 10C of SCN8A. Single nucleotide polymorphisms in intron 19 and exon 22 were also identified. We localized SCN8A to chromosome band 12q13.1 by physical mapping on a YAC contig. The cDNA clone CSC-1 was reported by others to be a cardiac-specific sodium channel, but sequence comparison demonstrates that it is derived from exon 24 of human SCN8A. The genetic information described here will be useful in evaluating SCN8A as a candidate gene for human neurological disease.
 ...
PMID:Exon organization, coding sequence, physical mapping, and polymorphic intragenic markers for the human neuronal sodium channel gene SCN8A. 982 31

The human genome contains 10 voltage-gated sodium channel genes, 7 of which are expressed in neurons of the CNS and PNS. The availability of human genome sequences and high-throughput mutation screening methods make it likely that many human disease mutations will be identified in these genes in the near future. Mutations of Scn8a in the mouse demonstrate the broad spectrum of neurological disease that can result from different alleles of the same sodium channel gene. Null mutations of Scn8a produce motor neuron failure, loss of neuromuscular transmission, and lethal paralysis. Less severe mutations result in ataxia, tremor, muscle weakness, and dystonia. The effects of Scn8a mutations on channel properties have been studied in the Xenopus oocyte expression system and in neurons isolated from the mutant mice. The Scn8a mutations provide insight into the mode of inheritance, effect on neuronal sodium currents, and role of modifier genes in sodium channel disease, highlighting the ways in which mouse models of human mutations can be used in the future to understand the pathophysiology of human disease.
 ...
PMID:Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. 1149 24

Scn8a encodes an abundant, widely distributed voltage-gated sodium channel found throughout the central and peripheral nervous systems. Mice with different mutant alleles of Scn8a provide models of the movement disorders ataxia, dystonia, tremor and progressive paralysis. We previously reported that the phenotype of the hypomorphic allele of Scn8a, medJ, is dependent upon an unlinked modifier locus, Scnm1. Strain C57BL/6J carries a sensitive allele of the modifier locus that results in juvenile lethality. We now provide evidence that the modifier acts on the splicing efficiency of the mutant splice donor site. Mutant mice display either 90% or 95% reduction in the proportion of correctly spliced mRNA, depending on modifier genotype. The abundance of the channel protein, Na(v)1.6, is also reduced by an order of magnitude in medJ mice, resulting in delayed maturation of nodes of Ranvier, slowed nerve conduction velocity, reduced muscle mass and reduction of brain metabolic activity. medJ mice provide a model for the physiological effects of sodium channel deficiency and the molecular mechanism of bigenic disease.
 ...
PMID:Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6). 1237 66

Early infantile epileptic encephalopathy type 13 is a severe form of epilepsy caused by mutations in the sodium channel 8 alpha (SCN8A) gene. This gene encodes the neuronal voltage-gated sodium channel which plays vital role in neuronal excitability. Here we present two cases with SCN8A encephalopathy. Both cases had mutation in p.Arg1872Gin the SCN8A gene, which was detected by targeted next generation sequencing. Case 1 was a 14-month old boy, who had a normal birth history with normal development up to 6 months and then developed repeated generalized seizure, which was nonresponsive to multiple antiepileptic drugs. He also had neuroregression and dystonia. His electroencephalogram (EEG) showed progressive background abnormality with burst suppression pattern. His metabolic panel was normal and had partial response to carbamazepine. The second case was for an 11-month old boy with the onset of seizure at the age of 7 months. Seizure was generalized, resistant to multiple antiepileptic drugs. He had developmental delay from beginning, no movement disorder. EEG showed focal discharge from left temporal and occipital region. He showed partial response to oxcarbazepine. Our cases had similarities with the previously reported cases. The detailed discussion of our cases would contribute to early detection and targeted treatment of SCN8A encephalopathy. This also gives special emphasis on a genetic test in infants with intractable epilepsy, movement disorder and developmental delay.
 ...
PMID:SCN8A Mutation in Infantile Epileptic Encephalopathy: Report of Two Cases. 3250 51