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Link to original content: https://www.ncbi.nlm.nih.gov/omim/605375
ORPHA: 98784; DO: 0060684;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q21.3 | Epilepsy, nocturnal frontal lobe, 3 | 605375 | 3 | CHRNB2 | 118507 |
A number sign (#) is used with this entry because of evidence that nocturnal frontal lobe epilepsy-3 (ENFL3) is caused by heterozygous mutation in the gene encoding the beta-2 nicotinic acetylcholine receptor (nAChR) subunit (CHRNB2; 118507) on chromosome 1q21.
Clustered attacks of epileptic episodes originating from the frontal lobe during sleep represent the main manifestation of autosomal dominant frontal lobe epilepsy (ENFL, ADNFLE) (summary by De Fusco et al., 2000).
For a general phenotypic description of autosomal dominant nocturnal frontal lobe epilepsy, see 600513.
Gambardella et al. (2000) reported a large 3-generation Italian family segregating autosomal dominant nocturnal frontal lobe epilepsy. The age at onset of seizures was around 9 years of age and all affected individuals manifested nocturnal partial seizures of frontal lobe origin.
In a large Italian family segregating ADNFLE, Gambardella et al. (2000) excluded linkage to known loci on chromosome 20 (600513) and chromosome 15 (603204) and established linkage to chromosome 1.
The transmission pattern of ADNFLE in the family reported by Gambardella et al. (2000) and De Fusco et al. (2000) was consistent with autosomal dominant inheritance with incomplete penetrance.
In affected members of the Italian family with ADNFLE reported by Gambardella et al. (2000), De Fusco et al. (2000) identified a heterozygous mutation in the CHRNB2 gene (V287L; 118507.0001). Eight members were affected and 5 were asymptomatic, suggesting incomplete penetrance of the disorder.
In affected members of a Scottish family with ADNFL3, Phillips et al. (2001) identified a different heterozygous mutation at the same codon in the CHRNB2 gene (V287M; 118507.0002).
Manfredi et al. (2009) developed and characterized a mouse model of ENFL3 carrying the V287L mutation (118507.0001) of the CHRNB2 gene. Mice expressing mutant receptors showed a spontaneous epileptic phenotype by electroencephalography with very frequent interictal spikes and seizures. Expression of the mutant protein was driven by a neuronal-specific tetracycline-controlled promoter, which allowed reversible planned silencing of transgene expression. Restricted silencing during development was sufficient to prevent the occurrence of epileptic seizures in adulthood. Manfredi et al. (2009) hypothesized that mutant nicotinic receptors are responsible for abnormal formation of neuronal circuits and/or long-lasting alteration of network assembly in the developing brain, thus leading to epilepsy.
De Fusco, M., Becchetti, A., Patrignani, A., Annesi, G., Gambardella, A., Quattrone, A., Ballabio, A., Wanke, E., Casari, G. The nicotinic receptor beta-2 subunit is mutant in nocturnal frontal lobe epilepsy. Nature Genet. 26: 275-276, 2000. [PubMed: 11062464] [Full Text: https://doi.org/10.1038/81566]
Gambardella, A., Annesi, G., De Fusco, M., Patrignani, A., Aguglia, U., Annesi, F., Pasqua, A. A., Spadafora, P., Oliveri, R. L., Valentino, P., Zappia, M., Ballabio, A., Casari, G., Quattrone, A. A new locus for autosomal dominant nocturnal frontal lobe epilepsy maps to chromosome 1. Neurology 55: 1467-1471, 2000. [PubMed: 11094099] [Full Text: https://doi.org/10.1212/wnl.55.10.1467]
Manfredi, I., Zani, A. D., Rampoldi, L., Pegorini, S., Bernascone, I., Moretti, M., Gotti, C., Croci, L., Consalez, G. G., Ferini-Strambi, L., Sala, M., Pattini, L., Casari, G. Expression of mutant beta-2 nicotinic receptors during development is crucial for epileptogenesis. Hum. Molec. Genet. 18: 1075-1088, 2009. [PubMed: 19153075] [Full Text: https://doi.org/10.1093/hmg/ddp004]
Phillips, H. A., Favre, I., Kirkpatrick, M., Zuberi, S. M., Goudie, D., Heron, S. E., Scheffer, I. E., Sutherland, G. R., Berkovic, S. F., Bertrand, D., Mulley, J. C. CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am. J. Hum. Genet. 68: 225-231, 2001. [PubMed: 11104662] [Full Text: https://doi.org/10.1086/316946]