ABSTRACT
More than 230 genes in the human genome are known to code for ion-channel subunits, and this number increases if auxiliary subunits are taken into account. Several highly conserved families of ion channels are known, including different classes of voltage-gated potassium, sodium, or chloride channels, and ligand-gated channels such as GABAA and acetylcholine receptors. Most ion-channel gene families have their origins in the earliest metazoans, but their largest increase in numbers took place in the vertebrate lineage where duplication events led to a multiplication of subunits in most families (Jegla et al. 2009). Ion channels are involved in nearly every physiological process and are the cause of many different rare and common disorders. Ion-channel mutations are mainly found in disorders that are caused by excitable cells, such as neurons, skeletal and smooth muscle, or heart muscle. Within the central nervous system, epilepsies constitute a major group of disorders associated with ion-channel mutations (Steinlein 2008). So far, at least 25 different ion-channel genes have been implicated with some form of epilepsy, and although many of these reports are still uncon–rmed, several epilepsy genes have by now been –rmly established. These include human
33.1 Introduction .......................................................................................................................... 451 33.2 Nicotinc Acetylcholine Receptors ........................................................................................ 452 33.3 Autosomal Dominant Nocturnal Frontal Lobe Epilepsy ..................................................... 453 33.4 Mutations in Neuronal nAChRs Cause ADNFLE ............................................................... 453 33.5 The Clinical Variability of ADNFLE .................................................................................. 454 33.6 Functional Consequences of ADNFLE Mutations ............................................................... 454
33.6.1 ADNFLE Mutations Cause a Gain of Function ....................................................... 455 33.6.2 NFLE Mutations in the α2 Gene .............................................................................. 455
33.7 What Genetically Modi–ed Animal Models Can Teach Us ................................................. 455 33.8 Possible Association between Mutations and Pharmacological Sensitivity ........................ 456 33.9 Future Directions .................................................................................................................. 456 References ...................................................................................................................................... 457
epilepsy genes such as SCN1A, coding for the α1 subunit of the voltage-gated sodium channel (Escayg et al. 2000), KCNQ2, one of the voltage-gated potassium channel subunits responsible for the action-potential-controlling M-current (Biervert et al. 1998), as well as the nicotinic acetylcholine receptors (nAChR) discussed in the following sections.
