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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.
Advances in the design and discovery of novel small molecule drugs for the treatment of Dravet Syndrome
Published in Expert Opinion on Drug Discovery, 2021
Barbara Miziak, Stanisław Czuczwar
In earlier indexes DS was listed as an idiopathic syndrome. It is now known that there is a strong genetic component to the cause of this disease. A real breakthrough with regards to DS causes was de novo discovery of dominant mutation of voltage-gated sodium-channel gene α 1 subunit (SCN1A). The same mutation type in its severe manifestation is also found in 85% of patients with DS [9,15–17]. Milder manifestations of this type of sodium-channel function disruption (NaV1.1) may also lead to unique epileptic syndrome designated as generalized epilepsy with febrile seizures plus (GEFS +), while the most delicate one is febrile seizures (FS). As stated above, the SCN1A gene is a voltage-gated sodium-channel (NaV1.1) α-1-subunit-coding gene located in gamma-aminobutyric acid (GABA) inhibitory interneurons which in the first year of life gradually replaces embryonic NaV1.3 channel. Heterologous expression of mutant channel points to the loss of its function which, in turn, contributes to neuronal hyperactivity found both in bipolar- and pyramidal-shaped neurons in DS patients. Mice models reflecting the impairment of NaV1.1 function in interneurons display also disinhibition. GABAergic interneurons are found in various locations in the brain which explains varying symptoms. Hence, the cortex cell dysfunction results in epileptic seizures, the problems in basal ganglia and motor neurons cause crouching gait, disorders in hypothalamus result in thermodysregulation, vegetative disorders and sleep troubles, and problems in cerebellum cause ataxia. The impaired functions of all of these structures will be manifested by disorders and psychomotor retardation [16,17].
Significance of DopEcR, a G-protein coupled dopamine/ecdysteroid receptor, in physiological and behavioral response to stressors
Published in Journal of Neurogenetics, 2020
Emily Petruccelli, Arianna Lark, James A. Mrkvicka, Toshihiro Kitamoto
Heat is another commonly experienced environmental stressor. Insects are ectotherms (“cold-blooded” organisms), and thus internal body temperatures are especially vulnerable to change in the ambient temperature. Since temperature has a significant impact on conductance and gating kinetics of ion channels (Kiernan, Cikurel, & Bostock, 2001; Buzatu, 2009; Chowdhury, Jarecki, & Chanda, 2014), heat treatment may acutely induce abnormalities in neural activity and behavior. Mutations in ion channel genes often increase the sensitivity to heat and result in heat-induced behavioral phenotypes such as paralysis and seizure. parats1, a recessive loss-of-function, temperature-sensitive mutation in the fly voltage-gated sodium channel gene paralytic (para), causes an immediate, but reversible, paralysis of adult flies when they are shifted from 22 °C to 29 °C (Suzuki, Grigliatti, & Williamson, 1971). paraGEFS+ is another para allele which harbors a gain-of-function mutation that mimics the human mutation underlying an epilepsy syndrome called generalized epilepsy with febrile seizures plus (GEFS+). Upon exposure to 40 °C homozygous or hemizygous paraGEFS+ flies display seizure-like behavior, including leg twitches, failure to maintain standing posture, wing buzzing, and occasional abdomen curling (Sun et al., 2012). Remarkably, we found that DopEcR mutants show behavioral changes reminiscent of paraGEFS+responses upon heat stress (Figure 2(A)). Mutants displayed robust heat-induced seizure-like behavior with ∼90% of homozygous DopEcRGal4null mutants and ∼40% of homozygous DopEcRPB1hypomorphic mutants showing seizure-like activity within two minutes of 40 °C heat treatment. After the onset of heat, DopEcRGal4flies rapidly lost postural control and fell over onto their backs. They often extended or buzzed their wings and repeatedly kicked their legs or curled their abdomens up into the air. DopEcR trans-heterozygotes (DopEcRGal4/DopEcRPB1) expectantly failed to compliment, and DopEcR appeared to be haplosufficient for this trait since heterozygous mutants (DopEcRGal4/+ and DopEcRPB1/+) showed little seizure-like behavior upon heat treatment (Figure 2(B)). Although DopEcR is required to maintain neuronal homeostasis under extreme heat, DopEcR mutants have normal heat place memory (Ostrowski, Kahsai, Kramer, Knutson, & Zars, 2015), suggesting that they have intact noxious heat sensation.