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Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
There are relatively few single gene disorders that result in inherited forms of epilepsy, and these are usually caused by mutations in ion channels or neurotransmitter genes. For example, severe myoclonic epilepsy of infancy is caused by mutations in the a1 subunit of the sodium channel gene SCN1A. Mutations in the b1 subunit of the sodium channel gene SCN1B may cause generalized epilepsy with febrile seizures-plus (GEFS +). Benign infantile neonatal epilepsy is caused by mutations in the potassium channel genes, KCNQ2 or KCNQ3. Juvenile myoclonic epilepsy has been associated with mutations in the chloride channel gene CLCN2.
Potassium channels as prominent targets and tools for the treatment of epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Out of a wide spectrum of potassium channels, voltage-gated potassium channels are the main focus in epilepsy research (Table 1). Mutations of genes encoding pore-forming or accessory subunits of the channels have been found in humans with epilepsy, mostly in relatively uncommon autosomal dominant epilepsies. Mutations of Kv7.2/7.3 channels are accepted to be linked with several forms of epilepsy, mainly with those with neonatal onset [50]. Multiple mutations of Kv7.2 channel have been associated with various epileptic phenotypes, ranging from the mild epileptic syndrome (benign familial neonatal epilepsy, BFNE) to early onset severe epileptic encephalopathy with pharmacoresistant seizures and neurological impairment (KCNQ2/Kv7.2 encephalopathy) [51–56]. A linkage between the phenotype of KCNQ2-associated epilepsy and gene location of pathogenic missense variants of KCNQ2 subunit [57] as well as the mutation-induced functional impairments [53,58] have been reported. Kv7.3 channel mutations were also identified in BFNE and benign familial infantile epilepsy with developmental delay and intellectual disability [59,60]. The degree of the functional impairment caused by mutations at position 330 in KCNQ3 is suggested to contribute to clinical disease severity [61].
Personalized treatment in the epilepsies: challenges and opportunities
Published in Expert Review of Precision Medicine and Drug Development, 2018
Simona Balestrini, Sanjay M Sisodiya
The KCNQ2 and KCNQ3 genes encode subunits of the voltage-gated potassium M channel underlying the neuronal M-current [60] and are amongst the most common causes of neonatal epileptic encephalopathy of widely varying severity [61]. In KCNQ2/KCNQ3-related epilepsy, there is a potential tailored precision medicine strategy with the use of retigabine (ezogabine), a drug primarily acting as a positive allosteric modulator of KCNQ2-5 (Kv7.2–7.5) ion channels, and the first neuronal potassium (K+) channel opener licensed for the treatment of epilepsy [62]. In vitro studies identified the probable binding site of retigabine in KCNQ2 and KCNQ3 channels, explaining its voltage-dependent activating effect through a hyperpolarizing shift of the activation curve [63]. Retigabine has been shown to partially reverse the effect of KCNQ2 mutations in cell models [64].
Genome-wide association studies on Northern Italy isolated populations provide further support concerning genetic susceptibility for major depressive disorder
Published in The World Journal of Biological Psychiatry, 2023
Vincenzo Dattilo, Sheila Ulivi, Alessandra Minelli, Martina La Bianca, Edoardo Giacopuzzi, Marco Bortolomasi, Stefano Bignotti, Massimo Gennarelli, Paolo Gasparini, Maria Pina Concas
KCNQ5 (OMIM 607357) gene encodes for a voltage-gated potassium channel, important for the regulation of the current modulating the neuronal excitability (Lehman et al. 2017). It belongs to the KV7 family of voltage-gated potassium channels, comprising five KCNQ members (KCNQ1-5) (Brown and Passmore 2009). Four KCNQ genes (KCNQ2-5) are expressed in the central nervous system both on RNA and protein level (Brown and Passmore 2009) and are therefore excellent candidate susceptibility genes for a wide range of neuronal disorders. Moreover, the expression of ion-channel subunits has been reported to be modulated in mice exposed to chronic psychotropic drugs as well as electroconvulsive treatment (ECT) (Duncan et al. 2008; Hjaeresen et al. 2008). KV7.5 can form heterotetrameric channels with KV7.3 (Schroeder et al. 2000). Some genetic variants of KCNQ3 leading to a functional impairing of the channel complex formed by KV7.3 and KV7.5 are reported in patients affected by MDD or other psychiatric and neurodevelopmental diseases (Gilling et al. 2013). A dominant-negative Kcnq5 mutation in mice has been shown to alter synaptic activity in the hippocampus, where the channel is highly expressed (Tzingounis et al. 2010; Fidzinski et al. 2015). Recently, transcriptomic analyses revealed dysregulation in the expression of KCNQ5 in patients with neurological and psychiatric diseases including MDD (Baird et al. 2021; Verma and Shakya 2021). On these bases, KCNQ5 could be a suggestive susceptibility gene for MDD and some typologies of neurological disorders, and due to the considerable overlap in aetiologies also for other psychiatric disorders including anxiety. Given the significance of ion channels in neuronal activity, neurotransmission, plasticity, and the formation of neuronal circuitry, which regulates major processes relevant to psychiatric disorders, the development of drugs modulating the ion-channel activity could counteract anhedonia and anergy that are often resistant to standard treatments in MDD (Smolin et al. 2012). Interestingly, KCNQ channel openers, including FDA-approved drug retigabine (ezogabine), have been proven to normalise the connectivity of brain circuitry reversing the depressive symptomatology through the potentiation of active resilience mechanisms (Friedman et al. 2016; Tan et al. 2018).