Pleiotropic functional effects of the first epilepsy‐associated mutation in the human CHRNA2 gene

Abstract

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) can be caused by mutations in the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4 and CHRNB2. Recently, a point mutation (alpha2-I279N) associated with sleep-related epilepsy has been described in a third nAChR gene, CHRNA2. We demonstrate here that alpha2-I279N can be co-expressed with the major structural subunit CHRNB2. alpha2-I279N causes a marked gain-of-function effect and displays a distinct biopharmacological profile, including markedly reduced inhibition by carbamazepine and increased nicotine sensitivity.

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…Epilepsy occurs in 5-49% of people with autism (Levy et al, 2009). Genetic abnormalities in CHRN4A and CHRNB2, encoding the  and  nAChR subunits respectively, are sufficient to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (De Fusco, 2000;Bertrand, 2002;Steinlein, 2002;Hoda, 2009) (Ross et al, 2000) and the 2 nAChR knockout animal shows abnormal sleep pattern (Lena et al, 2004). These studies demonstrate that behaviors regulated by nAChRs are disparate and commonly aberrant in ASD and suggest the potential for nAChR-acting drugs in the treatment of ASD.…”

Nicotinic receptor channelopathies and epilepsy

“…In this initial study, however, functional nAChRs were obtained only by expression of the α2 subunit with the β4 subunit and therefore differed from the native receptors that most likely mainly result from the assembly of α2 with β2. Further studies carried out with the I279N α2 mutant expressed with the control β2 confirmed the gain of acetylcholine sensitivity caused by this mutation together with additional modifications in the receptor properties such as a gain of sensitivity to nicotine and in the carbamazepine blockade [29].…”

Genetische Aspekte bei idiopathischen fokalen Epilepsien

“…Derzeit sind 4 Mutationen im CHRNA4-und 3 im CHRNB2-Gen (β 2 -Untereinheit) sowie eine weitere Mutation in der α 2 -Untereinheit (CHRNA2; [13,29,30]) beschrieben; hierbei sind die meisten in den porenformenden, transmembranä-ren M2-Segmenten lokalisiert. Hinsichtlich des Pathomechanismus wird eine erhöhte Acetylcholinsensitivität, also ein Funktionsgewinn, angenommen [13,31]. Thalamokortikale Schleifen haben für die rhythmische Aktivität während des Schlafs eine wichtige Bedeutung, insbesondere für Projektionen in den Frontallappen, an denen auch cholinerge Neurone beteiligt sind.…”