The complexities of CACNA1A in clinical neurogenetics

Hommersom, Marina; Prooije, Teije H van; Pennings, Maartje; Schouten, Meyke; Bokhoven, Hans van; Kamsteeg, Erik‐Jan; Warrenburg, B.P.C. van de

doi:10.1007/s00415-021-10897-9

Cited by 23 publications

(13 citation statements)

References 85 publications

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“…The CACNA1A gene encodes a subunit of the voltage-dependent P/Q-type calcium channel α-1A (Zhang et al 2020b ), and the CACNA1E gene encodes a subunit of the voltage-dependent R-type calcium channel α-1E (Helbig et al 2018 ). These genes are widely expressed throughout the central nervous system and are strongly associated with epilepsy and intellectual developmental disorders (Hommersom et al 2021 ; Royer-Bertrand et al 2021 ). In addition, CACNA1E is of potential therapeutic value in non-small cell lung cancer (Gao et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Network-Based Data Analysis Reveals Ion Channel-Related Gene Features in COVID-19: A Bioinformatic Approach

Zhang

Feng

2022

Biochem Genet

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Coronavirus disease 2019 (COVID-19) seriously threatens human health and has been disseminated worldwide. Although there are several treatments for COVID-19, its control is currently suboptimal. Therefore, the development of novel strategies to treat COVID-19 is necessary. Ion channels are located on the membranes of all excitable cells and many intracellular organelles and are key components involved in various biological processes. They are a target of interest when searching for drug targets. This study aimed to reveal the relevant molecular features of ion channel genes in COVID-19 based on bioinformatic analyses. The RNA-sequencing data of patients with COVID-19 and healthy subjects (GSE152418 and GSE171110 datasets) were obtained from the Gene Expression Omnibus (GEO) database. Ion channel genes were selected from the Hugo Gene Nomenclature Committee (HGNC) database. The RStudio software was used to process the data based on the corresponding R language package to identify ion channel-associated differentially expressed genes (DEGs). Based on the DEGs, Gene Ontology (GO) functional and pathway enrichment analyses were performed using the Enrichr web tool. The STRING database was used to generate a protein–protein interaction (PPI) network, and the Cytoscape software was used to screen for hub genes in the PPI network based on the cytoHubba plug-in. Transcription factors (TF)–DEG, DEG–microRNA (miRNA) and DEG–disease association networks were constructed using the NetworkAnalyst web tool. Finally, the screened hub genes as drug targets were subjected to enrichment analysis based on the DSigDB using the Enrichr web tool to identify potential therapeutic agents for COVID-19. A total of 29 ion channel-associated DEGs were identified. GO functional analysis showed that the DEGs were integral components of the plasma membrane and were mainly involved in inorganic cation transmembrane transport and ion channel activity functions. Pathway analysis showed that the DEGs were mainly involved in nicotine addiction, calcium regulation in the cardiac cell and neuronal system pathways. The top 10 hub genes screened based on the PPI network included KCNA2, KCNJ4, CACNA1A, CACNA1E, NALCN, KCNA5, CACNA2D1, TRPC1, TRPM3 and KCNN3. The TF–DEG and DEG–miRNA networks revealed significant TFs (FOXC1, GATA2, HINFP, USF2, JUN and NFKB1) and miRNAs (hsa-mir-146a-5p, hsa-mir-27a-3p, hsa-mir-335-5p, hsa-let-7b-5p and hsa-mir-129–2-3p). Gene-disease association network analysis revealed that the DEGs were closely associated with intellectual disability and cerebellar ataxia. Drug-target enrichment analysis showed that the relevant drugs targeting the hub genes CACNA2D1, CACNA1A, CACNA1E, KCNA2 and KCNA5 were gabapentin, gabapentin enacarbil, pregabalin, guanidine hydrochloride and 4-aminopyridine. The results of this study provide a valuable basis for exploring the mechanisms of ion channel genes in COVID-19 and clues for developing therapeutic strategies for COVID-19.

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Section: Discussionmentioning

confidence: 99%

Network-Based Data Analysis Reveals Ion Channel-Related Gene Features in COVID-19: A Bioinformatic Approach

Zhang

Feng

2022

Biochem Genet

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“…The CACNA1A gene encodes the P/Q-type voltagegated Ca2+ channel α1 subunit CaV2.1 and is involved in neurotransmitter release and synaptic plasticity [28,29]. CACNA1A has been reported to be associated with episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6 [30]. ZFYVE21 has been reported to be a complement inducer of NF-κB in endothelial cells [31]; however, its function in the nervous system is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA-sequence

Yoshizumi

Nishi

Igeta

et al. 2022

Preprint

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Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by the genomic expansions of CTG repeats, in which RNA-binding proteins, such as muscleblind-like protein, are sequestered in the nucleus, and abnormal splicing is observed in various genes. Although abnormal splicing reportedly occurs in the brains of patients with DM1, it is relation to the central nervous system symptoms is unknown. Several imaging studies have indicated substantial white matter (WM) defects in patients with DM1. Here, we performed RNA-sequencing and analysis of CTG repeat lengths in the frontal lobe of patients with DM1, separating the grey matter (GM) and WM, to investigate the splicing abnormalities in the DM1 brain, especially in the WM. The results demonstrated the number of repeats in the GM tended to be increase, with several genes showing similar levels of splicing abnormalities in the GM and WM, suggesting that the WM defects in DM1 are not only caused by aberrant splicing of GM RNA but also of WM RNA, which could be attributed to abnormal splicing of glial cell RNAs.

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“…Reduced penetrance and high degrees of intra-familial variability have been reported across all CACNA1A phenotypes. This family emphasizes the increasing complexity of variant interpretation and genetic counseling in relation to this gene (Angelini et al, 2019;Hommersom et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

Wong-Spracklen

Kolesnik-Taylor

Eck

et al. 2022

American J of Med Genetics Pt A

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Biallelic variants in CACNA1A have previously been reported in nine individuals (four families) presenting with epilepsy and cognitive impairments of variable severity and age-of-onset. Here, we describe a child who presented at 6 months of age with drugresistant epilepsy and developmental delay. At 10 years of age, she has profound impairments in motor function and communication. MRI was initially unremarkable, but progressed to severe cerebellar atrophy by age 3 years. Next Generation Sequencing and panel analysis identified a maternally inherited truncating variant c.2042_2043delAG, p.(Gln681ArgfsTer100) and paternally inherited missense variant c.1693G>A, p.(Glu565Lys). In contrast to previously reported biallelic cases, parents carrying these monoallelic variants did not display clear signs of a CACNA1Aassociated syndrome. In conclusion, we provide further evidence that biallelic CAC-NA1A variants can cause a severe epileptic and developmental encephalopathy with progressive cerebellar atrophy, and highlight complexities of genetic counseling in such situations.

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The complexities of CACNA1A in clinical neurogenetics

Cited by 23 publications

References 85 publications

Network-Based Data Analysis Reveals Ion Channel-Related Gene Features in COVID-19: A Bioinformatic Approach

Network-Based Data Analysis Reveals Ion Channel-Related Gene Features in COVID-19: A Bioinformatic Approach

Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA-sequence

Biallelic CACNA1A variants: Review of literature and report of a child with drug‐resistant epilepsy and developmental delay

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