Genetic T-type calcium channelopathies

Weiss, Norbert; Zamponi, Gerald W.

doi:10.1136/jmedgenet-2019-106163

Cited by 63 publications

(62 citation statements)

References 156 publications

(170 reference statements)

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“…In conclusion, this newly identified ΔI153 variant is the first to be reported to cause a complete loss of Ca v 3.2 channel function [40]. Although its pathogenic role in the context of ALS remains to be established, these findings add to the notion that rare CACNA1H variants represent a risk factor for ALS.…”

Section: Discussionmentioning

confidence: 64%

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACN A1H encoding for Ca v 3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Ca v 3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominantnegative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Ca v 3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Ca v 3.2 channel function. These findings add to the notion that loss-of-function of Ca v 3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

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Section: Discussionmentioning

confidence: 64%

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

et al. 2020

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“…The CACNA1G gene has been associated with various forms of cerebellar ataxia and neurological comorbidities [ 2 , 3 , 4 , 6 , 18 , 19 ]. Our study further validates CACNA1G in the group of pathogenic neuronal ion channel genes associated with DEE [ 20 , 21 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Human brain transcriptomics data ( ) suggest that Ca v 3.1 is expressed at high levels in the cerebellum, cerebral cortex, hypothalamus, and olfactory region. CACNA1G undergoes alternative splicing, generating unique Ca v 3.1 channel isoforms exhibiting differential biophysical characteristics capable of fine-tuning neuronal excitability in the CNS [ 19 , 29 , 30 , 31 ]. Isoform b is normally found in the fetal brain, whereas the transcripts of the longer splice variants predominate in the adult brain [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Novel Missense CACNA1G Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy

Berecki

Helbig

Ware

et al. 2020

IJMS

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The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Cav3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca2+ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes.

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“…Seizures have been noted as a comorbidity feature of neurodevelopmental disorders (Hyde and Weinberger, 1997;Canitano, 2007;Mula et al, 2008;Liao et al, 2018;Salpekar and Mula, 2018;Strasser et al, 2018), which overall may point to the emergence of a functionally impaired neuronal network. For many neurodevelopmental disorders, several genetic variations (both rare mutations as well as common variants) in the coding regions of ion channel genes have been identified and reviewed elsewhere (Imbrici et al, 2013;Schmunk and Gargus, 2013;Daghsni et al, 2018;Weiss and Zamponi, 2019). Interestingly, also the mechanisms described above to be involved in the transcriptional regulation of ion channels in epilepsy pathogenesis, have been observed in the regulation of ion channels in other neurodevelopmental diseases.…”

Section: Transcriptional Regulation Of Channelopathies In Neurodevelomentioning

confidence: 99%

Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies

Loo

Becker

2020

Front. Cell. Neurosci.

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Epilepsy is a common neurological disorder characterized by recurrent uncontrolled seizures and has an idiopathic "genetic" etiology or a symptomatic "acquired" component. Genetic studies have revealed that many epilepsy susceptibility genes encode ion channels, including voltage-gated sodium, potassium and calcium channels. The high prevalence of ion channels in epilepsy pathogenesis led to the causative concept of "ion channelopathies," which can be elicited by specific mutations in the coding or promoter regions of genes in genetic epilepsies. Intriguingly, expression changes of the same ion channel genes by augmentation of specific transcription factors (TFs) early after an insult can underlie acquired epilepsies. In this study, we review how the transcriptional regulation of ion channels in both genetic and acquired epilepsies can be controlled, and compare these epilepsy "ion channelopathies" with other neurodevelopmental disorders.

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Genetic T-type calcium channelopathies

Cited by 63 publications

References 156 publications

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

Novel Missense CACNA1G Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy

Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies

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