The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits
Introduction
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clustered attacks of brief motor seizures originating from the frontal lobe mostly during light sleep (Scheffer et al., 1995). The onset of the epilepsy is usually during childhood or adolescence, with a penetrance of 70–80%. Seizures are often, but not in all patients readily controlled by antiepileptic drugs, especially carbamazepine. Two genes have so far been identified in ADNFLE families (Fusco et al., 2000, Hirose et al., 1999, Leniger et al., 2003, Phillips et al., 2001, Steinlein et al., 1995), CHRNA4 and CHRNB2 encoding the α4 and β2 subunits of the nAChR, respectively. The nAChRs are members of the large family of ligand-gated ion channels and are constituted by the assembly of five subunits arranged pseudosymmetrically around the central axis that forms a cation-selective ion pore. Pharmacological and ligand-binding studies have shown that the different nAChRs vary in their distribution in brain and channel properties, depending on their subunit composition (Bertrand et al., 2002). Both α4 and β2 subunits are found in almost all brain regions, and the heteromeric α42/β23 receptor is thought to be the major high-affinity nicotine nAChR subtype in mammalian brain. In support of the recognized importance of the cholinergic system in higher brain functions, recent work has shown that nAChR mutations not only cause epilepsy but also can be associated with additional neurological or psychiatric features (Hirose et al., 1999, Cho et al., 2003, Magnusson et al., 2003). We present herein a new ADNFLE mutation in the CHRNB2 gene that is characterized by an unusual localization at the β2 protein level, and a clinical phenotype including nocturnal seizures and selective defects in memory performances.
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Patients and controls
Clinical data, results from neuropsychometric testing (performed at age 14 years), video-electroencephalography (video-EEG), MRI results, and DNA samples were obtained from both twin sisters (III3, III4, Fig. 1), now age 17. The parents (II1, II2) but not the twin's two older brothers (III1, III2) (age 23 and 19 years) were available for DNA testing.
Mutation analysis
DNA samples from both affected twins were used to screen the whole coding region of CHRNB2 for mutations. Primer pairs and PCR conditions have been
Clinical history
The twins (III3, III4, Fig. 1) were born following a normal pregnancy by cesarean section at 35 weeks. Both had normal motor development but needed speech therapy and were diagnosed as being dyslexic early. At the age of 7 years, nocturnal seizures started in both twins within a month. Initially, seizures occurred every 20 min throughout the night, and also during daytime naps. Therapy with sodium valproate stopped seizures for 4 to 5 years. Seizures recurred in both girls within months,
Discussion
The most interesting aspects of the nAChR mutation I312M are its unusual localization in the M3 segment of the β2 subunit and its association with both epilepsy and specific cognitive defects. The mutation was not found in the parents but occurred de novo in the twins. Both twins had specific problems with verbal memory tasks. Their performances in learning and recalling verbal material were significantly lower than expected from their general IQ. Such severe memory problems were not present in
Acknowledgments
This work was supported by a grant from the Nationales Genomforschungsnetz 2 (NGFN2) to OKS and by the Swiss National Science Foundation to DB.
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2020, Epilepsy and BehaviorCitation Excerpt :For example, the single-nucleotide polymorphism (SNP) C1545T in the CHRNA4 gene is associated with visuospatial attention deficits [97,98], and mutations in the α4 subunit, including S252L, T265I, and S248F, may affect core executive functions [94,99]. Mutations in β2 nAChR may affect general intellectual skills and verbal functions [96], and the missense mutation I312M in the CHRNB2 gene is associated with cognitive impairments, especially verbal memory deficiencies [96,100]. Steinlein et al. noted that the nAChR mutation-related risk for cognitive disorders was lower than the ADNFLE mutation-related risk [92].
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2016, Journal of Neuroscience MethodsCitation Excerpt :S284L-α4 and V287M-β2 variants caused a reduced dependence of the ACh response to Ca2+ and an increased sensitivity to ACh (Bertrand et al., 2002; Phillips et al., 2001; Rodrigues-Pinguet et al., 2003). Increased sensitivity to ACh was also caused by S280F-α4, L291dup-α4 and T293I-α4 mutations, and M301V-β2, V308A-β2 and I312M-β2 mutations (Bertrand et al., 2005, 2002; Hoda et al., 2008; Leniger et al., 2003), leading to activation of nAChRs at low concentrations of ACh, thus increasing their probability of opening (Bertrand et al., 2002; Hoda et al., 2008; Leniger et al., 2003; Phillips et al., 2001; Teper et al., 2007). In contrast, the effects of α2-mutations on nAChR properties are still uncertain since I279N-α2 resulted in a gain-of-function consisting of an increased sensitivity to the exogenous agonist nicotine (Aridon et al., 2006), whereas the I297F-α2 mutation caused a decreased nicotine-induced current (Conti et al., 2015), when expressed heterozygously in HEK-293T cells.
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Contributed equally.