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Table of Contents    
Year : 2021  |  Volume : 69  |  Issue : 4  |  Page : 808-816

Mutations in the Voltage Dependent Calcium Channel CACNA1A (P/Q type alpha 1A subunit) Causing Neurological Disorders - An Overview

Molecular Genetics and Cancer Biology Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India

Date of Submission31-Oct-2019
Date of Decision10-Jul-2020
Date of Acceptance18-Aug-2020
Date of Web Publication2-Sep-2021

Correspondence Address:
Sivasamy Ramasamy
Molecular Genetics and Cancer Biology Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore - 641 046, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.325378

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 » Abstract 

Background: The voltage-dependent calcium channel α1 subunit (CACNA1A) gene plays a major role in neuronal communication. Mutation in this gene results in altered Ca2+ ion influx that modify the neurotransmitter release resulting in the development of various neurological disorders like hemiplegic migraine with cortical spreading depression, epilepsy, episodic ataxia type 2, and spinocerebellar ataxia type 6.
Objective: This review aimed in portraying the frequent mutations in CACNA1A gene causing hemiplegic migraine with cortical spreading depression, epilepsy, episodic ataxia type 2 and spinocerebellar ataxia type 6.
Methodology: A systematic search has been adopted in various databases using the keywords “Calcium channel,” “migraine,” “epilepsy,” “episodic ataxia,” and “spinocerebellar ataxia” for writing this review that collectively focuses on mutations in the CACNA1A gene causing the common neurological diseases from 1975 to 2019.
Conclusion: Every type of mutation has its own signature in gene functioning and understanding them might aid knowing more in disease progression.

Keywords: Ataxia, CACNA1A, calcium, epilepsy, migraine, mutations
Key Message: Highlights the frequent mutations reported in the CACNA1A gene causing Hemiplegic migraine with cortical spreading depression, epilepsy, episodic ataxia type 2 and spinocerebellar ataxia type 6. Understanding the functional effect of these might aid in developing targeted drugs for effective treatment.

How to cite this article:
Manickam AH, Ramasamy S. Mutations in the Voltage Dependent Calcium Channel CACNA1A (P/Q type alpha 1A subunit) Causing Neurological Disorders - An Overview. Neurol India 2021;69:808-16

How to cite this URL:
Manickam AH, Ramasamy S. Mutations in the Voltage Dependent Calcium Channel CACNA1A (P/Q type alpha 1A subunit) Causing Neurological Disorders - An Overview. Neurol India [serial online] 2021 [cited 2021 Oct 18];69:808-16. Available from:

Passage of ions across the cell membranes is possible by the integral membrane proteins, and voltage-gated ion channels being one of them, plays a major role in neuronal cell communication.[1] The voltage across the transmembrane aids in opening and closing of channels including the four-domain voltage-gated Ca2+ (Cav) and Na+ (Nav) channels; one domain K+ channel and all these have very similar architecture.[2],[3],[4],[5] The Cav channel initiates different cellular responses due to the influx of Ca2+ ions, which initiates the transduction of signals on the surface of cell into information required to initiate intracellular responses.[6],[7],[8],[9] These responses include a wide range of processes like release of neurotransmitter, transcription of gene, activating the enzymes that are calcium-dependent etc.[10] Any sort of impairment in this process will eventually cause disorders associated with cardiac, muscular, visual and neurological systems that are mostly dependent on the calcium channel.[11]

In neurons, the Cav aids in synaptic transmission [Figure 1]. Depending on the intensity of action potential received at the neuronal end, an inflow of Ca2+ ions occurs through the Cav channel. This then mobilizes the immobilized synaptic vesicles to align themselves with the presynaptic membrane where a fusion takes place and an opening is formed. Here the neurotransmitters are released into the synaptic cleft and bind to the neurotransmitter receptors of the ligand-gated channel present on the surface of the post-synaptic neuron. Transfer of presynaptic potential takes place creating a nerve impulse that gets passed on to the nearby neuron until the destination is reached.[12],[13] Human inherited diseases involving the voltage-gated calcium channels are mainly centered around three main genes CACNA1A (Cav2.1 channel) along with CACNA1H (Cav3.2 channel) and CACNA1S (Cav1.1 channel).[14] Of these three genes, the CACNA1A aids in the making of the P/Q type alpha 1A subunit of the voltage-gated calcium channel predominantly expressed in neuronal tissue and so, in this review, we are focusing on the properties of CACNA1A gene in causing the neurological disorders.
Figure 1: Involvement of calcium ion channels in pre-synaptic vesicle mobilization during nerve impulse transmission

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 » Methodology Top

Articles studied for making this manuscript were gathered using a Boolean strategy from multiple search engines like Google Scholar, Elsevier, PubMed and Science Direct using keywords like “Calcium channel,” “migraine,” “epilepsy,” “episodic ataxia” and “spinocerebellar ataxia”. From all the results obtained, cited 143 references were chosen for making this review from 1975 to 2019 and they were cross-checked for perfection.


CACNA1A also known as the calcium channel voltage-dependent P/Q type alpha 1A subunit. This is the major ion channel gene encoding the pore-forming α1 subunit of the neuronal cell voltage gate Cav2.1 (P/Q- type channel)[10],[15],[16],[17] with 19p13 as its chromosomal location.[18] This channel plays a major role in nerve cell communication of the brain through neurotransmitter release. It also maintains the neuronal calcium signaling and homeostasis that shows effect on neuron excitability, gene transcription, synaptic plasticity, neurotransmitter release, apoptosis and survival.[19],[20] The P/Q-, N- and R-type Ca2+ (Ca) channels together functions in controlled release of neurotransmitters, and only the P/Q-type channel has a major role due to its exocytotic character.[10],[21],[22]

The developmental changes in the calcium channel with increase in age makes the excitation to be completely dependent on the P/Q-type channel.[23],[24] Ca-dependent facilitation and inactivation is made possible by the Cav2.1 channel by its interaction with many Ca-binding proteins.[25] When the mutation occurs in this channel [Figure 2], various neurological disorders arises such as hemiplegic migraine (HM) with cortical spreading depression[26],[27]; episodic ataxia type 2[28],[29],[30]; epilepsy[31],[32]; spinocerebellar ataxia type 6[33],[34] and the common mutations in them are discussed in [Table 1].
Figure 2: Portrays the overall disease pathway of the mutated CACNA1A gene discussed in the manuscript

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Table 1: Mutations reported so far in the CACNA1A gene in various neurological disorders

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Apart from this, some diseases with cognitive and behavioral alterations were reported to have deletion in the 19p13 region relating to CACNA1A position.[35] In pediatric syndromes with CACNA1A mutation, mental retardation and 19p13:2-13 deletion were reported.[35] A 19p13.13 deletion was observed in 16 individuals of four French family having symptoms of cognitive impairment.[36] Deletion in the 19p13 region was also reported in the double-mutant mouse model study for human idiopathic epilepsy having KCNA1 and CACNA1A gene.[37] Micro-deletion in the 19p13.13 is also reported in subjects with overgrowth, intellectual disability and macrocephaly.[38] The complete details of this CACNA1A gene (like its sequence, transcripts, variants, diseases associated etc.) is collectively mentioned in the database created by the Leiden University Medical Center (

Hemiplegic migraine with cortical spreading depression

HM is a rare type of headache characterized by partial paralysis along with aura. The subject experiences partial weakness that lasts from one hour to several days. Defective voltage-gated calcium channel plays a major role in causing hemiplegic migraine with cortical spreading depression. Usually, this P/Q type calcium channel helps in maintaining the controlled release of neurotransmitters through action potentials developed and they have an unique feature of Ca-dependent facilitation and Ca-dependent inactivation based on the amount of Ca-binding proteins[39] displaying normal cortical inhibitory-excitatory function. When a trigger happens, this normal inhibitory-excitatory function gets disturbed and the cortical circuits get hyper activated by the recurrent excitation thereby causing spontaneous cortical spreading depression (CSD).[40],[41]

Based on their pattern of occurrence HM is classified into sporadic and familial type (SHM and FHM) by the International Headache Society (IHS) in their International Classification of Headache disorder (ICHD).[42] Genetic study on HM maps the gene of familial type on chromosome 19.[18],[43],[44] Out of all migraine subtypes, genetics of HM is best explored that suggests the role of three major genes (ATP1A2, SCN1A, and CACNA1A) for this condition and with most subjects (50%) showing CACNA1A mutation.[45]

Mutated CACNA1A is known to cause HM and in some cases, it results in poor coordination and balance and epilepsy. Few common mutations in the CACNA1A in causing HM are T666M, S218L, and I1811L. In a 47-year-old Polish proband having severe headache and vomiting with hemiparesis, blurred vision and parethesias displayed the presence of a heterozygous T666M mutation (c. 1997C > T; T666M) with familial nature.[46] Combined effect of mutated T666M (located in the S5-S6 of domain II) and I1811L is found to influence the calcium channel inactivation[47] and is reported in HM subjects.[48] A case with S218L mutation having HM with epileptic seizures and cerebellar symptoms was reported[32] where EEG revealed the deprived action resembling hemiplegia due to altered calcium channel.[49],[50],[51]

A report on same S218L mutation of CACNA1A revealed the presence of cytotoxic oedema which is later found to show atrophic symptoms in the symptomatic hemisphere.[52] Magnetic resonance study on the Japanese family having missense T666M mutation reported its association with both HM and progressive cerebellar atrophy with distinct pathogenetic mechanism.[53],[54] Migraine with aura symptoms is mainly due to CSD, where there is a suppression in the brain activity due to depolarization event[55],[56] and reports on R192Q FHM type 1 mouse shows the involvement of cortical hyperexcitability in migraine subjects with aura and CSD.[27] Single nucleotide polymorphism (SNPs) of CACNA1A gene were determined in HM subjects and the result shows the presence of polymorphisms E918D and E993V, which influences the functioning of calcium P/Q-type channel resulting in HM.[57] A case study showing point mutation c. 1741G > C (change of Valine in the 581 position to Leucin), alters the voltage-sensing mechanism of the calcium channel, concluding that HM might be associated with late-onset cognitive decline added to other observations on mental retardation.[58] In addition to the point mutations discussed, several deletions in the CACNA1A gene were also found to cause both sporadic and familial hemiplegic migraine. A report shows that the sporadic cases have deletion in the exons 41-43 and in others, there is terminal deletion in CACNA1A gene.[59] A study on the child with SHM and non-episodic ataxia shows gain of function of CACNA1A gene due to deletion of phenylalanine at 1502 position.[60] Other mutations that results in following amino acid changes are observed in hemiplegic migraine subjects such as R583Q, V714A, R1347Q[61]; R192Q[45]; K469E[62]; Y1385C[63]; W1684R, R1668W.[64]


A neurological disorder with 3000 years of history and 1% prevalence rate, epilepsy is characterized by spontaneous episodes of seizures due to hyperexcitation of neurons affecting the quality of life in people belonging to various age groups, races and regions.[65],[66],[67] The pathophysiology of epilepsy involves imbalance in the glutamate and Gamma-Aminobutyric Acid (GABA) mediated neurotransmission.[65] The susceptibility of the disease has been proved by examining the familial component that leads to understanding the involvement of genetics behind its progression. Various genes have been discovered so far through the genome wide association studies, helping in eliminating most of the mysteries behind the disease. Out of all the genes discovered, the CACNA1A mutation draws the attention of the researchers due to its involvement in the voltage-gated P/Q-type calcium channel.[68],[69],[70]

The impaired neuronal excitability being a major cause of epilepsy, involves the calcium channel with its remarkable function in the presynaptic and postsynaptic levels; alterations in them might have a probable role in epilepsy progression.[71] Neuronal excitability and CACNA1A is more closely associated in case of epilepsy because of the synaptic efficacy and neurotransmission function of the P/Q-type channel.[72] Although many studies reported the involvement of T-type channel in epilepsy, numerous mutations in the P/Q-type is channel is reported.[73]

Research on Chinese Han population identified 5 major SNPs in the CACNA1A of epileptic subjects which includes rs2074880, rs10416717, rs7254351, rs16030, and rs2248069 but their exact role in causing epilepsy still remains a mystery.[74] Another study on a year-old boy with myoclonic epilepsy reported the presence of missense mutation in the CACNA1A gene which might be a possible cause for early-onset encephalopathy.[31] In a study involving the genetic analysis of the epileptic encephalopathy, the CACNA1A gene is found to have a c. 2137G > A mutation with the A713T amino acid change, proving its role in causing epileptic encephalopathy.[75] Since seizure has been found to be associated with many neurological diseases, genetic association study on diseases having epileptic seizures revealed the presence of many point mutations in the CACNA1A gene to have major role in its cause. The familial hemiplegic and episodic ataxia are the major conditions having epileptic seizure as a common symptom; the genetic studies by various researchers around the world has reported mutations like S218L[76]; A712T, E101Q, A1511S, S1373L, R477H, R1967Q, Q1397X[77]; R1673C[78]; Y1385C[79]; R1668W[15],[80]; W1684R[81]; I1710T[82]; T666M[83]; R1820X,[84],[85] E714K.[86]

Episodic ataxia type 2

Episodic ataxia (EA) is a rare, autosomal dominant, familial disorder characterized by paroxysmal attacks usually associated with the jerking movements of arms, legs, and head.[87] Emotional and physical stress are the main triggers in the expression of associated clinical symptoms.[88] Studies on the genes that leads to the progression of disease identified the involvement of the voltage-gated potassium channel Kv1.1, a main reason behind familial nature of the EA.[89] Reports show that EA-2 is also mainly characterized by cerebellar ataxia with symptoms like migraine that improves with the treatment of acetazolamide[90] which is prescribed mainly to diseases involving potassium channel dysfunction.

Out of the eight types of EA (EA 1-8), EA1 is caused by mutation in the KCNA1 gene,[91] EA2 by CACNA1A gene,[28],[92] EA5 by CACNB4 gene,[93] EA6 by SLC1A3 gene[94] and the genetic background of EA7 and EA8 is still under exploration. The most studied type of EA is the EA-2, which is caused mainly due to mutation in the CACNA1A gene. The characteristics of EA-2 is mainly dependent on the type of point and bulk mutations found in the CACNA1A gene.[95] Mutation in the Cav2.1α1 subunit reduces the calcium current in the P/Q-type channel which in turn reduces the pacemaking property of the purkinje cells.[96] This reduces the Purkinje cell's ability to encode the motor-related information, which in turn cause EA2 symptoms.[97]

A study on HM and EA-2 reported mutations in the CACNL1A4 gene.[16] In the absence of mutation, the CAG expansion in the CACNA1A gene cause permanent cerebellar deficit along with low level of instability due to change in the allele size.[98] Not only point mutation has been reported in EA-2 subjects, but few studies marked the presence of deletion of several exons of CACNA1A gene.[17],[99],[100] An interesting study reported the presence of guanine deletion in the nucleotide 5123 (delG5123) which alters the reading frame during translation that results in the appearance of stop codon.[101]

A novel mutation, IVS36–2A>G, at the 3' acceptor splice site in the 36th intron of CACNA1A gene had been reported in the Finnish EA-2 family which is recorded to be the most mutated region in the C-terminal.[102] A unique nonsense mutation which leads to early appearance of stop code in the 1547 position of CACNA1A gene by a change of base from C to T at the 4914 position of the 29th exon has been identified.[103] G293R and C287Y are the two-pore missense mutations found to alter the normal functioning of the CaV2.1 channel.[104] Although many studies suggest the role of mutated CACNA1A gene in EA-2, there is an interesting study that describes no association of mutated CACNA1A in a family with EA-2 reporting the probable role of other genes in causing this disease.[105] Other mutations reported are G297R, R198Q, c. 3102 + 2T > C, C3089 + 2T > C, R1785X[35]; R1661H[78]; H253Y, F1406C[106]; F1493S[107]; E1761K, G540R, R1281X, Q2039X, R1549X[108]; R1824X, R1669X[109]; Q1154X[110]; c. 2867_2869del.[36]

Spinocerebellar ataxia type 6

Characterized by slow degeneration of the cerebellum (mainly the brainstem) and other parts of the central nervous system, the spinocerebellar ataxia (SCA) has autosomal dominant mode of inheritance.[111] There are around 40 types of SCA reported and the number continues to increase and when looked into the genetic background, the SCA can be categorized into three major forms like those having usual mutations (missense, deletion, insertion, etc.); those with repeats of non-protein-coding regions; and those with expanded CAG portions.[112] Involvement of Kv3.3 ion channel plays a major role in the progression of this condition.[113]

Apart from the reported potassium channel involvement, the alpha 1A subunit of the voltage-dependent calcium channel has an important role in SCA disease progression. In the case of SCA6, mutation in the CACNA1A is noted to alter the Purkinje cells by altering the calcium homeostasis in the cerebellum thereby triggering the symptoms of SCA.[114] Among various mutations reported, CAG repeat expansion mutation (more than 22 repeats) was observed in the affected individuals.[115],[116] Mutation in more than 50 genes was reported to cause SCA but the exact mechanism of these protein products in SCA development was not clearly determined until the calcium channel disruption was identified.[117] CAG repeats is the major reason behind SCA6 progression, and in exon 13 of the CACNA1A gene substitution of G to A is observed that results in amino-acid change from arginine to glutamine at the 583rd position.[118] Abnormal CAG repeat length was observed in the SCA6 subject in the 47th exon of the CACNA1A gene which causes aggregation of CaV2.1 channel protein in the cytoplasm.[119] Reports show that in the SCA6 subjects, there are only 21-33 CAG repeats which are very less compared to other polyglutamine diseases thus proving the presence of other factors responsible for causing the disease.[120] Cognitive impairment in the SCA6 subjects was also found to be linked with mutations in the gene located in the 19th chromosome like that of the CACNA1A gene.[121],[122] In the SCA2 subjects, the variation in the polyglutamine number of the CACNA1A gene is found to be linked with the modification in the age of onset.[123] R1664Q is observed in subjects having hypotonia, cerebellar atrophy, developmental delay, etc.[78] Based on all the existing reports, it is concluded that only the SCA6 is more influenced by the mutation in the CACNA1A gene.

 » Conclusion Top

Neurotransmission is one of the major factors that aids in normal functioning of the body. Any disruption in the neurotransmission will cause some kind of malfunction depending on the type of ion channel affected. As discussed above, the voltage-gated calcium channel plays a major role in neurotransmission and though the complete mechanism of the voltage-gated calcium channel have been described in causing the above-discussed neurological diseases, complete cure to such diseases are still lacking. Since mutation is one of the main reasons behind calcium channel malfunction, further development is needed in designing site-specific/target-oriented strategy to alter such mutations thereby, restoring the normal functioning of the channel. Further advancements in exploring the proteins of the ion channel are much needed as these are the ones that are in direct action with the body functioning. Recent research on exploring the ion channels on mitochondrial membrane will shed some light on the therapeutic approaches that can be developed in the future.

Financial support and sponsorship

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

There are no conflicts of interest.


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