241:. As with the S248F mutation, the L259_I260insL mutation is located in the second transmembrane spanning region. Electrophysiological experiments have shown that this mutant is tenfold more sensitive to acetylcholine than wild-type. Calcium permeability, however, is notably decreased in mutant compared to wild-type containing receptors. Furthermore, this mutant shows slowed desensitization compared to both wild-type and S248F mutant receptors.
380:
341:
113:
299:, which encodes an acetylcholine receptor β2 subunit. Two of these mutations, V287L and V287M, occur at the same amino acid, again in the second transmembrane spanning region. The V287L mutation results in receptors that desensitize at a much slower rate compared to wild-type. The V287M mutant displays a higher affinity for acetylcholine when compared to wild-type receptors. As with the mutations in
516:
Matsushima N, Hirose S, Iwata H, Fukuma G, Yonetani M, Nagayama C, Hamanaka W, Matsunaka Y, Ito M, Kaneko S, Mitsudome A, Sugiyama H (2002). "Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor alpha 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the
206:
at a much faster pace compared to wild-type only receptors. These mutant containing receptors also recover from desensitization at a much slower rate than wild-type only receptors. These mutant receptors also have a decreased single channel conductance than wild-type and have a lower
252:
associated with ADNFLE is T265M, again located in the second transmembrane spanning segment. This mutation has been little studied and all that is known is that it produces receptors with increased sensitivity to acetylcholine and has a low penetrance.
244:
Also located in the second transmembrane spanning region, the S252L mutation has also been associated with ADNFLE. This mutant displays increased affinity for acetylcholine faster desensitization compared to wild-type receptors.
470:, Wallace R, Phillips H, Sutherland G, Scheffer I, Berkovic S (1995). "A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy".
80:. These seizures often involve complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as
939:
Phillips H, Scheffer I, Crossland K, Bhatia K, Fish D, Marsden C, Howell S, Stephenson J, Tolmie J, Plazzi G, Eeg-Olofsson O, Singh R, Lopes-Cendes I, Andermann E, Andermann F, Berkovic S, Mulley J (1998).
989:
De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, Quattrone A, Ballabio A, Wanke E, Casari G (2000). "The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy".
310:
is I312M, located in the third membrane-spanning region. Receptors containing these mutant subunits display much larger currents and a higher sensitivity to acetylcholine than wild-type receptors.
1124:
Aridon P, Marini C, Di Resta C, Brilli E, De Fusco M, Politi F, Parrini E, Manfredi I, Pisano T, Pruna D, Curia G, Cianchetti C, Pasqualetti M, Becchetti A, Guerrini R, Casari G (2006).
855:
Hirose S, Iwata H, Akiyoshi H, Kobayashi K, Ito M, Wada K, Kaneko S, Mitsudome A (1999). "A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy".
423:
El Helou J, Navarro V, Depienne C, Fedirko E, LeGuern E, Baulac M, An-Gourfinkel I, Adam C (2008). "K-complex-induced seizures in autosomal dominant nocturnal frontal lobe epilepsy".
615:"Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human alpha4beta2 nicotinic acetylcholine receptors"
1081:
Bertrand D, Elmslie F, Hughes E, Trounce J, Sander T, Bertrand S, Steinlein O (2005). "The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits".
84:. Attacks often occur in clusters and typically first manifest in childhood. There are four known loci for ADNFLE, three with known causative genes. These genes,
566:"An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics"
1255:
669:"Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy"
1265:
1126:"Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear"
1204:
820:, Bertrand D (1997). "An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy".
1032:
Phillips H, Favre I, Kirkpatrick M, Zuberi S, Goudie D, Heron S, Scheffer I, Sutherland G, Berkovic S, Bertrand D, Mulley J (2001).
195:
97:
723:
Bertrand D, Picard F, Le
Hellard S, Weiland S, Favre I, Phillips H, Bertrand S, Berkovic S, Malafosse A, Mulley J (2002).
151:
plays a vital role in ADNFLE. The reasons for this belief are threefold. Firstly, thalamocortical loops are important in
1034:"CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy"
942:"Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24"
203:
1250:
1245:
328:. This mutant shows a higher sensitivity to acetylcholine and unchanged desensitization compared to wild-type.
194:
transition at position 248 (S248F), located in the second transmembrane spanning region of the gene encoding a
1240:
208:
230:. This mutation, L259_I260insL, is caused by the insertion of three nucleotides (GCT) between a stretch of
164:
1260:
769:"Five ADNFLE mutations reduce the Ca2+ dependence of the mammalian alpha4beta2 acetylcholine response"
577:
202:
protein, this mutation is called S280F. Receptors containing this mutant subunit are functional, but
148:
1106:
1014:
880:
542:
495:
448:
324:, which encodes a nicotinic acetylcholine receptor α2 subunit similar to the nAChR α4 encoded by
69:
320:
Recently, the I279N mutation has been discovered in the first transmembrane spanning segment of
1155:
1098:
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Rodrigues-Pinguet N, Jia L, Li M, Figl A, Klaassen A, Truong A, Lester H, Cohen B (2003).
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1177:
GeneReviews/NCBI/NIH/UW entry on
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
499:
816:
Steinlein O, Magnusson A, Stoodt J, Bertrand S, Weiland S, Berkovic S, Nakken K,
784:
436:
898:
Leniger T, Kananura C, Hufnagel A, Bertrand S, Bertrand D, Steinlein O (2003).
1176:
1094:
900:"A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy"
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81:
45:
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subunits comprise the three known causative genes for ADNFLE. Thirdly,
73:
17:
187:
1141:
1049:
957:
667:
Bertrand S, Weiland S, Berkovic S, Steinlein O, Bertrand D (1998).
1002:
152:
77:
269:
around it. Instead some of these families show strong linkage on
1218:
1215:
1212:
1209:
613:
Kuryatov A, Gerzanich V, Nelson M, Olale F, Lindstrom J (1997).
374:
335:
147:
While not well understood, it is believed that malfunction in
107:
303:, these mutants lead to receptors less sensitive to calcium.
215:. Also importantly, this mutation along with the others in
762:
760:
171:
are almost invariably present at the start of seizures.
725:"How mutations in the nAChRs can cause ADNFLE epilepsy"
390:
351:
261:
Some families have been shown to not have mutations in
123:
159:
is the origin of ADNFLE seizures. Secondly, both the
1186:
1190:
198:α4 subunit. Using the numbering based on the human
51:
39:
34:
285:. Causative genes in this area are still unknown.
226:The second discovered ADNFLE mutation was also in
62:Autosomal dominant nocturnal frontal lobe epilepsy
35:Autosomal dominant nocturnal frontal lobe epilepsy
511:
509:
718:
716:
714:
712:
662:
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186:The first mutation associated with ADNFLE is a
8:
295:Three mutations have been found in the gene
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163:and cortex receive cholinergic inputs and
31:
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1057:
965:
915:
792:
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692:
640:
630:
589:
248:The most recently discovered mutation in
415:
560:Weiland S, Witzemann V, Villarroel A,
7:
517:rat receptor expressed in oocytes".
219:produce receptors less sensitive to
632:10.1523/JNEUROSCI.17-23-09035.1997
25:
1256:Unsolved problems in neuroscience
917:10.1046/j.1528-1157.2003.61102.x
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339:
196:nicotinic acetylcholine receptor
111:
98:nicotinic acetylcholine receptor
742:10.1046/j.1528-1157.43.s.5.16.x
1:
591:10.1016/S0014-5793(96)01215-X
531:10.1016/S0920-1211(01)00336-9
265:and, furthermore, to show no
72:that causes frequent violent
1266:Autosomal dominant disorders
785:10.1113/jphysiol.2003.036681
437:10.1016/j.clinph.2008.07.212
306:The other known mutation in
1282:
1095:10.1016/j.nbd.2005.05.013
466:Steinlein O, Mulley J,
685:10.1038/sj.bjp.0702154
564:, Steinlein O (1996).
387:This section is empty.
348:This section is empty.
165:acetylcholine receptor
120:This section is empty.
869:10.1212/wnl.53.8.1749
149:thalamocortical loops
834:10.1093/hmg/6.6.943
735:(Suppl 5): 112–22.
582:1996FEBSL.398...91W
484:10.1038/ng1095-201
104:Signs and symptoms
100:α and β subunits.
70:epileptic disorder
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425:Clin Neurophysiol
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96:, encode various
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29:Medical condition
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1142:10.1086/506459
1130:Am J Hum Genet
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1038:Am J Hum Genet
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952:(4): 1108–16.
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519:Epilepsy Res
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26:
576:(1): 91–6.
235:amino acids
204:desensitize
52:Usual onset
1235:Categories
818:Propping P
619:J Neurosci
562:Propping P
468:Propping P
410:References
371:Management
239:isoleucine
82:nightmares
991:Nat Genet
904:Epilepsia
857:Neurology
773:J Physiol
729:Epilepsia
570:FEBS Lett
472:Nat Genet
398:July 2024
359:July 2024
332:Diagnosis
175:Mechanism
169:K-complex
131:July 2024
55:Childhood
46:Neurology
41:Specialty
1160:16826524
1111:29811931
1103:15964197
1068:11104662
1019:21818633
1011:11062464
926:12823585
885:27745257
877:10563623
803:12754307
751:12121305
547:36484761
539:11904236
453:26640365
445:18762450
209:affinity
161:thalamus
155:and the
74:seizures
68:) is an
1151:1559502
1059:1234917
976:9758605
967:1377480
842:9175743
794:2343021
703:9831911
694:1571006
651:9364050
642:6573611
600:8946959
578:Bibcode
492:7550350
267:linkage
237:and an
232:leucine
221:calcium
76:during
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1210:600513
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326:CHRNA4
322:CHRNA2
315:CHRNA2
308:CHRNB2
301:CHRNA4
297:CHRNB2
290:CHRNB2
283:CHRNB4
281:, and
279:CHRNA5
275:CHRNA3
263:CHRNA4
250:CHRNA4
228:CHRNA4
217:CHRNA4
200:CHRNA4
188:serine
181:CHRNA4
143:Causes
94:CHRNA2
92:, and
90:CHRNB2
86:CHRNA4
66:ADNFLE
18:ADNFLE
1107:S2CID
1015:S2CID
881:S2CID
543:S2CID
496:S2CID
449:S2CID
257:15q24
153:sleep
78:sleep
1205:OMIM
1156:PMID
1099:PMID
1064:PMID
1007:PMID
972:PMID
922:PMID
873:PMID
838:PMID
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747:PMID
699:PMID
647:PMID
596:PMID
535:PMID
488:PMID
441:PMID
211:for
1146:PMC
1138:doi
1091:doi
1054:PMC
1046:doi
999:doi
962:PMC
954:doi
912:doi
865:doi
830:doi
789:PMC
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777:550
737:doi
689:PMC
681:doi
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