Biallelic <i>CACNA2D2</i> variants in epileptic encephalopathy and cerebellar atrophy

Punetha, Jaya; Karaca, Ender; Gezdirici, Alper; Lamont, Ryan E.; Pehlivan, Davut; Marafi, Dana; Appendino, Juan Pablo; Hunter, Jill V.; Akdemir, Zeynep Coban; Fatih, Jawid M.; Jhangiani, Shalini N.; Gibbs, Richard A.; Innes, A. Micheil; Posey, Jennifer E.; Lupski, James R.

doi:10.1002/acn3.50824

Cited by 22 publications

(13 citation statements)

References 28 publications

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“…Epilepsy was reported in 51.6% (82/159) of the cases. Ten calcium channelopathies related to ID/GDD were identified involving the following genes: CACNA1A [ 18 , 19 , 39 – 66 ], CACNA1C [ 67 – 73 ], CACNA1I [ 74 ], CACNA1H [ 75 , 76 ] , CACNA2D2 [ 77 – 80 ], CACNA2D1 [ 20 , 81 ], CACNA1D [ 21 , 22 , 82 – 84 ], CACNA1E [ 85 ], CACNA1F [ 86 ], and CACNA1G [ 23 , 87 ]. The underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits.…”

Section: Resultsmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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Section: Resultsmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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“…Seizure/epilepsy related proteins (shaded cells in Table 3 and Table 4 ) include: SLIT2 (Slit guidance ligand 2 [ 29 ]), EPHB2 (EphrinB receptor 2, [ 30 ]), LAMA2 (Laminin alpha-2, [ 31 ]), ADAM11 (ADAM (A disintegrin and metalloprotease domain 11, [ 32 ]), P2RX7 (Purinergic receptor P2X 7, [ 33 ]), SLC4A4 (Solute carrier family 4 member 4, [ 34 ]), KCNQ2 (Potassium Voltage-Gated Channel Subfamily Q Member 2, [ 9 ]), VWF (von Willebrand factor, [ 35 ]), RYR2 (Ryanodine receptor 2, [ 36 ]), RECK (Reversion Inducing Cysteine Rich Protein With Kazal Motifs, [ 37 ]), ATP7B (ATPase Copper Transporting Beta, [ 38 ]), NF1 (Neurofibromin 1, [ 39 ]), HDC (Histidine Decarboxylase, [ 40 ]). Two other important seizure/epilepsy related proteins in Table 3 and Table 4 are CACNA2D2 (Calcium Voltage-Gated Channel Auxiliary Subunit Alpha2 delta 2, [ 41 ]) and ASTN2 (Astrotactin 2, [ 42 ]). Both these proteins have ion-channel functions which have important roles in epileptogenesis [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

Distinguishing and Biochemical Phenotype Analysis of Epilepsy Patients Using a Novel Serum Profiling Platform

et al. 2020

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Diagnosis of non-symptomatic epilepsy includes a history of two or more seizures and brain imaging to rule out structural changes like trauma, tumor, infection. Such analysis can be problematic. It is important to develop capabilities to help identify non-symptomatic epilepsy in order to better monitor and understand the condition. This understanding could lead to improved diagnostics and therapeutics. Serum mass peak profiling was performed using electrospray ionization mass spectrometry (ESI-MS). A comparison of sera mass peaks between epilepsy and control groups was performed via leave one [serum sample] out cross-validation (LOOCV). MS/MS peptide analysis was performed on serum mass peaks to compare epilepsy patient and control groups. LOOCV identified significant differences between the epilepsy patient group and control group (p = 10−22). This value became non-significant (p = 0.10) when the samples were randomly allocated between the groups and reanalyzed by LOOCV. LOOCV was thus able to distinguish a non-symptomatic epilepsy patient group from a control group based on physiological differences and underlying phenotype. MS/MS was able to identify potential peptide/protein changes involved in this epilepsy versus control comparison, with 70% of the top 100 proteins indicating overall neurologic function. Specifically, peptide/protein sera changes suggested neuro-inflammatory, seizure, ion-channel, synapse, and autoimmune pathways changing between epilepsy patients and controls.

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“…It is unclear if the impaired electrical activity associated with reduced α 2 δ-2 expression in SH-SY5Y overexpressing CLN1 relates to the abnormal firing of neuronal cells in other experimental settings. It is worth remarking, however, that biallelic variants in CACNA2D2 are detected in an early onset form of epileptic encephalopathy, which shares some clinical features with CLN1 disease (Brill et al, 2004 ; Ivanov et al, 2004 ; Punetha et al, 2019 ). Recent evidence suggests that the effects of CACNA2D2 on axonal growth and elongation as well as on synaptic formation are inhibited by pregabalin, a drug which targets the α 2 δ-2 subunit and which is used in several neurological conditions, including epilepsy (Tedeschi et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Profile Remodeling via Selective Suppression of Voltage-Gated Currents by CLN1/PPT1 Overexpression in Human Neuronal-Like Cells

Demontis

Pezzini

Margari

et al. 2020

Front. Cell. Neurosci.

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CLN1 disease (OMIM #256730) is an inherited neurological disorder of early childhood with epileptic seizures and premature death. It is associated with mutations in CLN1 coding for Palmitoyl-Protein Thioesterase 1 (PPT1), a lysosomal enzyme which affects the recycling and degradation of lipid-modified (S-acylated) proteins by removing palmitate residues. Transcriptomic evidence from a neuronal-like cellular model derived from differentiated SH-SY5Y cells disclosed the potential negative roles of CLN1 overexpression, affecting the elongation of neuronal processes and the expression of selected proteins of the synaptic region. Bioinformatic inquiries of transcriptomic data pinpointed a dysregulated expression of several genes coding for proteins related to voltage-gated ion channels, including subunits of calcium and potassium channels (VGCC and VGKC). In SH-SY5Y cells overexpressing CLN1 (SH-CLN1 cells), the resting potential and the membrane conductance in the range of voltages close to the resting potential were not affected. However, patch-clamp recordings indicated a reduction of Ba2+ currents through VGCC of SH-CLN1 cells; Ca2+ imaging revealed reduced Ca2+ influx in the same cellular setting. The results of the biochemical and morphological investigations of CACNA2D2/α2δ-2, an accessory subunit of VGCC, were in accordance with the downregulation of the corresponding gene and consistent with the hypothesis that a lower number of functional channels may reach the plasma membrane. The combined use of 4-AP and NS-1643, two drugs with opposing effects on Kv11 and Kv12 subfamilies of VGKC coded by the KCNH gene family, provides evidence for reduced functional Kv12 channels in SH-CLN1 cells, consistent with transcriptomic data indicating the downregulation of KCNH4. The lack of compelling evidence supporting the palmitoylation of many ion channels subunits investigated in this study stimulates inquiries about the role of PPT1 in the trafficking of channels to the plasma membrane. Altogether, these results indicate a reduction of functional voltage-gated ion channels in response to CLN1/PPT1 overexpression in differentiated SH-SY5Y cells and provide new insights into the altered neuronal excitability which may underlie the severe epileptic phenotype of CLN1 disease. It remains to be shown if remodeling of such functional channels on plasma membrane can occur as a downstream effect of CLN1 disease.

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Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy

Cited by 22 publications

References 28 publications

Calcium channelopathies and intellectual disability: a systematic review

Calcium channelopathies and intellectual disability: a systematic review

Distinguishing and Biochemical Phenotype Analysis of Epilepsy Patients Using a Novel Serum Profiling Platform

Electrophysiological Profile Remodeling via Selective Suppression of Voltage-Gated Currents by CLN1/PPT1 Overexpression in Human Neuronal-Like Cells

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