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)

Mutations of genes encoding alpha4, beta2, or alpha2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The mRNA level of the transgene (mutant Chrna4) was similar to the wild type, and no distorted expression was detected in the brain. However, the transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The therapeutic response of these rats to conventional antiepileptic drugs also resembled that of NFLE patients with the S284L mutation. The rats exhibited two major abnormalities in neurotransmission: (1) attenuation of synaptic and extrasynaptic GABAergic transmission and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice; thus, our transgenic rats offer another dimension to the epilepsy research field.
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PMID:Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype. 1902 39

Nocturnal frontal lobe epilepsy is seen exclusively during sleep and is characterized by three distinct seizure phenotypes: paroxysmal arousals, paroxysmal dystonia, and episodic wandering. Mutations of CHRNA4, CHRNB2, or CHRNA2 genes encoding alpha4, beta2 or alpha2 subunits of neuronal nicotinic ACh receptor (nAChR) have been identified in the individuals with sporadic type NFLE and pedigrees with autosomal dominant type of NFLE (ADNFLE). In the past decade, various electrophysiological studies have analyzed the functional abnormalities of ADNFLE/NFLE mutant nAChR; however, the detailed pathogenesis of ADNFLE/NFLE has remained to be clarified. Therefore, to explore the pathogenesis of ADNFLE/NFLE, genetic animal models harboring ADNFLE mutant Chrna4 genes have recently been established. The face, construct and predictive validities have been demonstrated in a transgenic rat strain bearing the S284L mutant Chrna4 gene. The in vivo analyses of the functional abnormalities using genetic ADNFLE/NFLE animal models suggest the putative mechanisms of the ADNFLE/NFLE seizure onset during slow wave sleep.
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PMID:[Generation of epilepsy animal model bearing a genetic abnormality identified in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) of humans]. 2029 37