CACNA1A and Associated Diseases

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Overview

CACNA1A gene is selectively spliced at multiple sites in age, sex, and species-dependent manner. Its encoded neuronal P/Q type Ca_V2.1 porogen subunit is widely expressed in the central nervous system (CNS), especially in Purkinje cells and cerebellar granule cells. Ca_V2.1 α1 subunit combining with different auxiliary β subunits and α2σ subunits result in functional diversity of Ca_V2.1 channels. The combination of subunits further leads to the functional diversity of the Ca_V2.1 channel. The Ca_V2.1 channel is located at the front of the glutamate synapse in the cortex and plays an important role in controlling the release of neurotransmitters. This gene mutation can cause a series of diseases, including sporadic ataxia type 2 (EA2) and familial hemiplegic migraine (FHM).

Fig.1 The distribution of 7 CACNA1A variants in the Ca_V2.1 channel. (Zhang, 2020)

Function of CACNA1A

Ca_V2.1 has been proven to have vital functions in many parts of the brain. Its expression in the cerebral cortex is particularly high. Ca_V2.1 channels play an important role in initial synaptic action potential-induced neurotransmitter release in the central nervous system. It is required by most pyramidal neurons for excitatory synaptic transmission, and this channel also influences some inhibitory transmission. Ca_V2.1 is also selectively conjugated to calcium-activated potassium channels (KCa) in cerebellar Purkinje cells. Ca_V2.1 channels are expressed in all brain structures associated with migraine and/or migraine pathogenesis. In the trigeminal vascular system, it plays an important role in the release of neurotransmitters from pain receptors in the meninges. In the cerebellum, P/ q type Ca²⁺ channels play a dominant role in initiating fast transmitter release at the synapses of excitatory parallel fibers (PF) and climbing fibers (CF) on the PCs.

CACNA1A in Diseases

The spectrum of CACNA1A disorders includes many autosomal dominant allelic disorders, which are characterized by multiple combinations of sporadic and chronic neurological signs. Chronic neurological symptoms include cerebellar ataxia, developmental delays, and varying degrees of cognitive and psychiatric symptoms. P/Q voltage-dependent calcium channel CACNA1A mutation causes paroxysmal ataxia, cerebellar atrophy in humans, recessive ataxia, dominant migraine, paroxysmal dyskinesia, cerebellar atrophy, and absence of epilepsy in mice.

• FHM and EA2 are caused by distinct types of mutations within CACNA1A.

The FHM and EA2 are both caused by mutations within CACNA1A. FHM is a genetically heterogenous condition for which two genes have been mapped so far, on chromosomes 19 and 1. Only CACNA1A has been identified. On the other hand, all EA2 families are connected to chromosome 19.

Fig.2 Mutations in CACNA1A causing hemiplegic migraine. (Ducros, 2001)

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References

1. Zhang, L.; et al. CACNA1A gene variants in eight Chinese patients with a wide range of phenotypes. Frontiers in Pediatrics. 2020, 8: 577544.
2. Ducros, A.; et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. New England Journal of Medicine. 2001, 345(1): 17-24.