Pathogenic Cav3.2 channel mutation in a child with primary generalized epilepsy

Souza, Ivana A.; Gandini, María A.; Zhang, Fang-Xiong; Mitchell, Wendy G.; Matsumoto, Joyce H.; Lerner, Jason T.; Pierson, Tyler Mark; Zamponi, Gerald W.

doi:10.1186/s13041-019-0509-5

Cited by 11 publications

(6 citation statements)

References 28 publications

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“…Most of the previous studies focused on the effects of Cav3.2 on neuronal firing activity control in the regulation of anxiety [ 20 ], memory [ 20 ], chronic pain [ 11 ], and epilepsy [ [21] , [22] , [23] ]. However, the role of Cav3.2 in feeding behavior and energy homeostasis is still not well understood.…”

Section: Introductionmentioning

confidence: 99%

Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity

Feng

Harms

Patel

et al. 2021

Molecular Metabolism

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Objective Cav3.2, a T-type low voltage-activated calcium channel widely expressed throughout the central nervous system, plays a vital role in neuronal excitability and various physiological functions. However, the effects of Cav3.2 on energy homeostasis remain unclear. Here, we examined the role of Cav3.2 expressed by hypothalamic GABAergic neurons in the regulation of food intake and body weight in mice and explored the underlying mechanisms. Methods Male congenital Cana1h (the gene coding for Cav3.2) global knockout (Cav3.2KO) mice and their wild type (WT) littermates were first used for metabolic phenotyping studies. By using the CRISPR-Cas9 technique, Cav3.2 was selectively deleted from GABAergic neurons in the arcuate nucleus of the hypothalamus (ARH) by specifically overexpressing Cas9 protein and Cav3.2-targeting sgRNAs in ARH Vgat (Vgat ARH ) neurons. These male mutants (Cav3.2KO-Vgat ARH ) were used to determine whether Cav3.2 expressed by Vgat ARH neurons is required for the proper regulation of energy balance. Subsequently, we used an electrophysiological patch-clamp recording in ex vivo brain slices to explore the impact of Cav3.2KO on the cellular excitability of Vgat ARH neurons. Results Male Cav3.2KO mice had significantly lower food intake than their WT littermate controls when fed with either a normal chow diet (NCD) or a high-fat diet (HFD). This hypophagia phenotype was associated with increased energy expenditure and decreased fat mass, lean mass, and total body weight. Selective deletion of Cav3.2 in Vgat ARH neurons resulted in similar feeding inhibition and lean phenotype without changing energy expenditure. These data provides an intrinsic mechanism to support the previous finding on ARH non-AgRP GABA neurons in regulating diet-induced obesity. Lastly, we found that naringenin extract, a predominant flavanone found in various fruits and herbs and known to act on Cav3.2, decreased the firing activity of Vgat ARH neurons and reduced food intake and body weight. These naringenin-induced inhibitions were fully blocked in Cav3.2KO-Vgat ARH mice. Conclusion Our results identified Cav3.2 expressed by Vgat ARH neurons as an essential intrinsic modulator for food intake and energy homeostasis, which is a potential therapeutic target in the treatment of obesity.

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Section: Introductionmentioning

confidence: 99%

Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity

Feng

Harms

Patel

et al. 2021

Molecular Metabolism

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“…The gene CACNA1H encodes the α1 pore-forming subunit of Cav3.2 [41]. However, it remains ambiguous whether CACNA1H variants are a cause of monogenic epilepsy or not.…”

Section: Mutation Of Calcium Channelmentioning

confidence: 99%

“…Ivana A. Souza Et al. reported a child with primary generalized epilepsy caused by variants in CACNA1H [41]. Therefore, whether CACNA1H can cause epilepsy is controversial.…”

Section: Mutation Of Calcium Channelmentioning

confidence: 99%

An advance about the genetic causes of epilepsy

Sun

et al. 2021

E3S Web Conf.

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Human hereditary epilepsy has been found related to ion channel mutations in voltage-gated channels (Na+, K+, Ca2+, Cl-), ligand gated channels (GABA receptors), and G-protein coupled receptors, such as Mass1. In addition, some transmembrane proteins or receptor genes, including PRRT2 and nAChR, and glucose transporter genes, such as GLUT1 and SLC2A1, are also about the onset of epilepsy. The discovery of these genetic defects has contributed greatly to our understanding of the pathology of epilepsy. This review focuses on introducing and summarizing epilepsy-associated genes and related findings in recent decades, pointing out related mutant genes that need to be further studied in the future.

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“…In humans, several studies have reported associations between CACNA1H single nucleotide polymorphisms (SNPs) and epileptic phenotypes, especially in idiopathic generalized epilepsy (IGE) [42,69,87,138], reviewed in [158,167], since the first report by Chen et al [37] describing CACNA1H SNPs in childhood absence epilepsy (CAE) patients. Functional studies of several of these CACNA1H missense variants revealed that they could modify biophysical properties or protein trafficking of Cav3.2 in heterologous expression systems [69,154,155], in a loss-or gain-of-function manner.…”

Section: Cacna1h/cav32 In Epilepsymentioning

confidence: 99%

Neuronal Cav3 channelopathies: recent progress and perspectives

Lory

Nicole

Monteil

2020

Pflugers Arch - Eur J Physiol

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T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knockout mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to a variety of neurodevelopmental, neurological, and psychiatric diseases designated here as neuronal Cav3 channelopathies. In this review, we describe and discuss the clinical findings and supporting in vitro and in vivo studies of the mutant channels, with a focus on de novo, gain-of-function missense mutations recently discovered in CACNA1G and CACNA1H. Overall, the studies of the Cav3 channelopathies help deciphering the pathogenic mechanisms of corresponding diseases and better delineate the properties and physiological roles Cav3 channels.

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Pathogenic Cav3.2 channel mutation in a child with primary generalized epilepsy

Cited by 11 publications

References 28 publications

Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity

Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity

An advance about the genetic causes of epilepsy

Neuronal Cav3 channelopathies: recent progress and perspectives

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