CACNA2D1

The CACNA2D1 gene encodes a subunit of voltage-dependent calcium channels, which are essential for regulating calcium entry into cells. These channels play a key role in muscle contraction, neurotransmitter release, and normal heart function. Variants in CACNA2D1 have been linked to cardiac arrhythmias, epilepsy, and other neurological or cardiovascular disorders.

Biological Function

The CACNA2D1 encodes an auxiliary subunit of voltage-gated calcium channels: α2δ-1. α2δ-1 is abundant in synapses and plays a key role in calcium channel membrane targeting. Recent studies showed that this protein enhances synapse formation.

Mutations

Developmental delay and epilepsy conditions-linked mutations: Large-scale genetic sequencing studies have identified rare de novo variants in CACNA2D1 in individuals with neurodevelopmental phenotypes (e.g., p.Arg351Cys, p.Gly209Ser) identified in patients with developmental delay and epilepsy. De novo truncating mutations were found in developmental delay cohorts as well.
Mutations linked with Schizophrenia: Rare disrupting mutations have been found in patients with schizophrenia in one of the most important studies of the disease published. A de novo deletion of CACNA2D1 has been found in a patient with late-onset schizophrenia associated with tremors since childhood.

Associated Conditions

Rare variants in CACNA2D1 have been reported in patients with drug-resistant epilepsy, particularly early-onset epilepsy and epileptic encephalopathy. The main neurological syndrome is Developmental and Epileptic Encephalopathy 110 (DEE110).
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Dahimene et al. (2022) reported this association in patients with epilepsy and encephalopathy.
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Research at Northwestern

Penzes' lab has characterized a synthetic soluble form of α2δ-1, finding reduced levels in the cerebrospinal fluid of schizophrenia patients, and demonstrated promising improvements in social and cognitive performance in a mutant mouse model linked with schizophrenia.
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