Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

Striessnig, Jörg

doi:10.3389/fnsyn.2021.634760

Cited by 35 publications

(38 citation statements)

References 202 publications

(386 reference statements)

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“…The observed phenotype in the affected individuals reflected the typical course of an epileptic encephalopathy with the beginning of multiple seizure types in the first days of life as well as various degrees of intellectual disability. The pathophysiological mechanisms linking such a set of functionally heterogeneous genotypes with this devastating clinical picture are unclear (93). Detected variants include both newly described and well-known ones, such as the S218L, which is typically associated with a severe form of FHM1 (70).…”

Section: Epileptic Encephalopathy Clinical Presentation and Genotype-mentioning

confidence: 99%

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing

Indelicato

Boesch

2021

Front. Neurol.

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Ion channel dysfunction is a key pathological substrate of episodic neurological disorders. A classical gene associated to paroxysmal movement disorders is CACNA1A, which codes for the pore-forming subunit of the neuronal calcium channel P/Q. Non-polyglutamine CACNA1A variants underlie familial hemiplegic ataxia type 1 (FHM1) and episodic ataxia type 2 (EA2). Classical paroxysmal manifestations of FHM1 are migraine attacks preceded by motor aura consisting of hemiparesis, aphasia, and disturbances of consciousness until coma. Patients with EA2 suffer of recurrent episodes of vertigo, unbalance, diplopia, and vomiting. Beyond these typical presentations, several reports highlighted manifold clinical features associated with P/Q channelopathies, from chronic progressive cerebellar ataxia to epilepsy and psychiatric disturbances. These manifestations may often outlast the burden of classical episodic symptoms leading to pitfalls in the diagnostic work-up. Lately, the spreading of next generation sequencing techniques linked de novo CACNA1A variants to an even broader phenotypic spectrum including early developmental delay, autism spectrum disorders, epileptic encephalopathy, and early onset paroxysmal dystonia. The age-dependency represents a striking new aspect of these phenotypes und highlights a pivotal role for P/Q channels in the development of the central nervous system in a defined time window. While several reviews addressed the clinical presentation and treatment of FHM1 and EA2, an overview of the newly described age-dependent manifestations is lacking. In this Mini-Review we present a clinical update, delineate genotype-phenotype correlations as well as summarize evidence on the pathophysiological mechanisms underlying the expanded phenotype associated with CACNA1A variants.

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Section: Epileptic Encephalopathy Clinical Presentation and Genotype-mentioning

confidence: 99%

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing

Indelicato

Boesch

2021

Front. Neurol.

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“…They lead to increased Ca 2+ influx into the presynaptic terminal, enhanced neurotransmission, and neuronal hyperexcitability. [ 8 ] Most pathogenic variants in CACNA1A are missense variants lying in significant functional domains of the calcium channel, that is, the voltage sensor, pore, and pore-lining loops. The closest pathogenic mutation to codon 1379 reported here was Y1384C.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing identified a novel CACNA1A I1379F variant in a familial hemiplegic migraine type 1 pedigree

Luan

Zhang

2021

Medicine

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Rationale: Familial hemiplegic migraine (FHM) is a rare, autosomal dominant migraine with aura. CACNA1A encodes the α1A subunit of P/Q-type voltage-gated calcium channels, and its mutations have been associated with a wide spectrum of episodic and chronic neurological disorders, including FHM type 1 (FHM1). Patient concerns: A Chinese girl and some of her relatives who presented with hemiplegia with or without migraine were found to carry a novel heterozygous missense variant, I1379F, in CACNA1A by whole-exome sequencing. The variant consegregated with the disease and was predicted to be pathogenic. Diagnosis: The patient was diagnosed with FHM1 clinically and genetically. Interventions: Prophylactic therapy with flunarizine 5 mg daily was prescribed to the patient. Outcomes: Therapy with flunarizine was terminated after a few weeks. The intensity of the attacks was the same as before. Lessons: This case indicates that FHM should be considered when a patient manifests with episodic hemiplegia without migraine. In addition, genetic testing is an indispensable method to identify atypical attacks of hemiplegic migraine.

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“…As the selective inhibition of Ca V channel subtypes shows promising results to overcome a wide range of cellular dysfunctions by specifically addressing regions of the channel required for proper function, e.g., the pore-forming region, several drugs are being tested in the context of SARS-CoV-2 infections. A short discussion thereof is provided in Section 3.1 , while more detailed information about Ca2v channel blockers is presented in [ 40 ] as well as [ 41 ].…”

Section: Calcium Ion Channels and Sars-cov-2mentioning

confidence: 99%

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

Berlansky

Sallinger

Grabmayr

et al. 2022

Cells

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). This respiratory illness was declared a pandemic by the world health organization (WHO) in March 2020, just a few weeks after being described for the first time. Since then, global research effort has considerably increased humanity’s knowledge about both viruses and disease. It has also spawned several vaccines that have proven to be key tools in attenuating the spread of the pandemic and severity of COVID-19. However, with vaccine-related skepticism being on the rise, as well as breakthrough infections in the vaccinated population and the threat of a complete immune escape variant, alternative strategies in the fight against SARS-CoV-2 are urgently required. Calcium signals have long been known to play an essential role in infection with diverse viruses and thus constitute a promising avenue for further research on therapeutic strategies. In this review, we introduce the pivotal role of calcium signaling in viral infection cascades. Based on this, we discuss prospective calcium-related treatment targets and strategies for the cure of COVID-19 that exploit viral dependence on calcium signals.

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Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

Cited by 35 publications

References 202 publications

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing

From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing

Next-generation sequencing identified a novel CACNA1A I1379F variant in a familial hemiplegic migraine type 1 pedigree

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

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