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Am J Hum Genet
2001 Jan 01;681:225-31. doi: 10.1086/316946.
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CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy.
Phillips HA, Favre I, Kirkpatrick M, Zuberi SM, Goudie D, Heron SE, Scheffer IE, Sutherland GR, Berkovic SF, Bertrand D, Mulley JC.
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Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon, idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. We describe a mutation of the beta2 subunit of the nicotinic acetylcholine receptor, effecting a V287M substitution within the M2 domain. The mutation, in an evolutionary conserved region of CHRNB2, is associated with ADNFLE in a Scottish family. Functional receptors with the V287M mutation are highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity. CHRNB2 is a new gene for idiopathic epilepsy, the second acetylcholine receptor subunit implicated in ADNFLE.
Figure 1. Scottish family, with family members carrying the mutated CHRNB2 codon287 indicated by “m”
Figure 2. DNA sequence of CHRNB2, showing the c1025G→A transition. The upper chromatogram shows the mutation. The lower chromatogram shows the control sequence.
Figure 3. Similarities within the M2 domain. Codon 287, located near the extracellular end of the M2 domain, is indicated by the box.
Figure 4. A, left panel, Neuronal α4β2 heteropentameric receptor resulting from the assembly of two α4 and three β2 subunits. Right panel, α4β2 is shown as a pentamer with two potential ACh-binding sites. “β2*” identifies the V287M amino acid substitution. The ACh receptor can assemble without any mutated β2 subunit (α4β2 wild-type receptor) or with one, two, or three mutated β2* subunits. B, upper panel, Current traces elicited by consecutive applications of four or five increasing ACh concentrations (horizontal bars). The values above each bar indicate the concentration of ACh applied to the cell. Lower panel, Differences in ACh affinity are emphasized in a log-log plot. The logarithm of the absolute value of the current (measured in the upper panel, Log [−I]) is plotted as a function of the logarithm of ACh concentrations (Log [ACh]). −I and [ACh] are expressed in nA and nM, respectively. Values are mean ± SEM, with n=9 (α4β2), n=17 (α4β2*), and n=10 (α4[β2*+β2]). Solid lines are the best linear regression throughout data points. C, upper panel, Representative macroscopic currents recorded in oocytes expressing either the wild-type or mutated β2 subunit. Currents evoked by four ACh concentrations (0.1, 0.2, 0.8 and 8 μM) are superimposed. Cells were held at −100 mV and challenged with ACh (10 s) once every 120 s. Bars indicate ACh applications. Lower panel, ACh activation curves for α4β2, α4β2* and α4(β2*+β2). Dose-response curves were normalized to the maximal current amplitude of each cell. Values are mean ± SEM. For each ACh concentration, 3–8 independent measurements were averaged. Values of the curve fits are given in the text.
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