Calcium channelopathies and intellectual disability: a systematic review

Abstract

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.

Keywords: Calcium channelopathies; Cerebellar atrophy; Epilepsy; Genes; Global developmental delay; Intellectual disability; Review; Variants.

Fig. 1

A summary of the steps used for the literature selection

Fig. 2

Effects and locations of genetic aberrations for CACNA1A. There is a cluster of four critical residues in S4 transmembrane segment of domain III. Round yellow dots represent gain-of- function variants. Triangular yellow dots represent loss-of-function variants

Fig. 3

Location of the identified CACNA1C amino acid substitutions. There is a cluster of four critical residues in the DI/D II intracellular interlinker. Round yellow dots represent gain-of- function variants

Fig. 4

Location of the identified CACNA1D amino acid substitutions. There is a cluster of three critical residues in the domain I/domain II intracellular interlinker. Round yellow dots represent gain-of- function variants

Fig. 5

Location of the identified CACNA1E amino acid substitutions. There is a cluster of five critical residues important for gating in S6 transmembrane segment of domain II. Round yellow dots represent gain-of- function variants

Fig. 6

Location of the identified CACNA1G amino acid substitutions. Round yellow dots represent gain-of- function variants

Fig. 7

Location of the identified CACNA1H amino acid substitutions. Round yellow dots represent gain-of- function variants

Fig. 8

Location of the identified CACNA2D2 amino acid substitutions. Triangular yellow dots represent loss-of-function variants

Fig. 9

The mechanism of how gain-of-function variants can lead to ID/GDD. Calcium ions can enter into neuronal cell via Cav1.2, Cav1.4, Cavα2δ, Cav2.1, Cav2.2, Cav2.3, Cav3.1, Cav3.2 and Cav3.3. In normal physiology, some of the calcium ions go to the nucleus to initiate gene transcription, translation and protein synthesis essential for learning and memory, some go to mitochondria for ATP synthesis (essential for learning and memory) and some to the endoplasmic reticulum (ER) for storage. Gain-of- function variants can allow excessive influx of calcium ions inside the cells. This will reduce the amount of ATP production while contributing to the accumulation of reactive oxygen species (ROS) and release of cytochrome C that induces apoptosis of neuronal cell. Many red and blue solid circles stand for high calcium levels

Fig. 10

A summary of how loss-of- function variants can lead to autophagy. Calcium ions can enter into neuronal cell via Cav1.2, Cav1.4, Cavα2δ, Cav2.1, Cav2.2, Cav2.3, Cav3.1, Cav3.2 and Cav3.3. In normal physiology, some of the calcium ions go to the nucleus to initiate gene transcription, translation and protein synthesis essential for learning and memory, some go to mitochondria for ATP synthesis (essential for learning and memory) and some to the endoplasmic reticulum for storage. Calcium stored in the endoplasmic reticulum (ER) is used when there is minimal/no influx of calcium ions inside the cells. Autophagy occurs when there is metabolic stress such as low ATP and nutrient starvation. Low levels of calcium ions inside the neuronal cell being due to loss-of- function of calcium channels or due to depletion in ER can activate autophagy pathway. Low calcium entrance in the mitochondria will lead to low production of ATP which will activate the AMP-activated protein kinase (AMPK, a sensor of energy levels) and mTOR complex 1 (mTORC1) which in turn induce autophagy. Likewise, low calcium levels from the ER can activate calmodulin-dependent protein kinase kinase β (CaMKKβ) and then AMPK leading to autophagy. Dotted arrows signify low levels. Few red solid circles stand for low calcium ions levels