CACNA1E and Associated Diseases

CACNA1E encodes the α1-E subunit of the voltage-dependent calcium channel family member Cav 2.3. This subunit confers Cav 2.3 high-voltage activation, rapidly inactivating R-type current properties, and is widely expressed throughout the central nervous system to initiate rapid synaptic transmission.

Structure and Function of CACNA1E

CACNA1E is a voltage-gated calcium channel (VGCC) of which ten isoforms have been identified and characterized. VGCC is a multi-subunit complex composed of α-1, α-2, β and δ subunits in the same ratio, in which the α-1 subunit forms the entrance for calcium to enter the cell and determines the current of the channel characteristic. CACNA1E is widely distributed in the hippocampus, retina, islet cells, spleen, and kidney, which is classified as an R-type calcium channel for the current properties it generated. The CACNA1E channel activated at high voltage mediates calcium ions into excitable cells, and then intervenes in a variety of calcium-dependent biological processes. CACNA1E participates in neuronal firing, regulates neural information processing, and controls muscle contraction, hormone release, cell movement, gene expression, cell cycle, etc. CACNA1E is insensitive to stimulation by dihydropyridines (DHP), but can be blocked by SNX-482.

CACNA1E in Insulin Secretion

Calcium channels are essential for neuronal function, and different channel types tend to have different functions. High-voltage-activated Cav 2.3 channels mediate the entry of Ca²⁺ into cells in response to membrane depolarization, in addition to mediating fast synapses delivery, Cav 2.3 is expressed in pancreatic beta cells and plays a key role in second-phase insulin release, and silencing of Cav 2.3 expression significantly attenuates glucose-stimulated insulin secretion.

CACNA1E in Diseases

It has long been proved that the variation of the VGCC gene is closely related to human neurological diseases, and the advancement of gene sequencing technology in recent years has proven the phenotypic and functional consequences of CACNA1E variation.

All currently identified patients with CACNA1E mutations have similar clinical features, including severe developmental impairment, hyperkinetic movement disorders, joint spasms, intractable epilepsy in infancy, and severe axial hypotonia. Molecular genetic testing revealed highly consistent gain-of-function effects of missense variants of CACNA1E, including an increase in current density, promoting voltage-dependent activation, and delaying inactivation, a variant often associated with an autosomal linear inheritance pattern. In addition, genotype-phenotype correlations were also found between variant loci present in the CACNA1E gene for movement disorders, severe intellectual disability, or macrocephaly.

Although the relationships between the variation of CACNA1E and many diseases have been confirmed by statistics and gene sequencing methods, little is known about CACNA1E other than its unique high activation threshold and slow kinetics, especially the specific molecular mechanism of its mutation leading to such a severe neurological disease.

Fig 1. Secondary structure of the Cav2.3 channel with the distribution of disease-causing missense variants. (Helbig, 2018)

With a strong platform for genetic engineering and biological research, Creative Biolabs provides one-stop gene therapy services for the CACNA1E gene and associated diseases. We believe that through our comprehensive services, you can further explore the downstream mechanism of the CACNA1E gene and bring your physiological or pathological research to a deeper level.

Reference

1. Helbig, K.L.; et al. De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias. The American Journal of Human Genetics. 2018, 103: 666-678.