ArticleBrain : a journal of neurology2022
Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.
Article in Brain : a journal of neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- N-Type Ca Channel in Epileptic Syndromes and Epilepsy: A Systematic Review of Its Genetic Variants.International journal of molecular sciences · 2023Pooled it
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- A biallelic mutation in CACNA2D2 associated with developmental and epileptic encephalopathy affects calcium channel-dependent as well as synaptic functions of αJournal of neurochemistry · 2025Article
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- Voltage-gated calcium channels in genetic epilepsies.Journal of neurochemistry · 2024Review
- Autism-Linked Mutations in αPharmaceuticals (Basel, Switzerland) · 2024Article
- A Map of Transcriptomic Signatures of Different Brain Areas in Alzheimer's Disease.International journal of molecular sciences · 2024Article
- Novel heterozygous mutation of CACNA2D1 gene in a Chinese family with arrhythmia.BMC cardiovascular disorders · 2024Article
- A Novel Ubiquitin Ligase Adaptor PTPRN Suppresses Seizure Susceptibility through Endocytosis of NaAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights.Journal of neurology · 2024Review
- α2δ1-mediated maladaptive sensory plasticity disrupts adipose tissue homeostasis following spinal cord injury.Cell reports. Medicine · 2024Article
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- AAV-based gene therapy ameliorated CNS-specific GPI defect in mouse models.Molecular therapy. Methods & clinical development · 2024Article
- The SMA Modifier Plastin 3 Targets Cell Membrane-Associated Proteins in Motoneurons.Neuroscience insights · 2024Article
- Optical genome mapping identifies a homozygous deletion in the non-coding region of the SCN9A gene in individuals from the same family with congenital insensitivity to pain.Frontiers in genetics · 2024Article
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
Voltage-gated calcium (CaV) channels form three subfamilies (CaV1-3). The CaV1 and CaV2 channels are heteromeric, consisting of an α1 pore-forming subunit, associated with auxiliary CaVβ and α2δ subunits. The α2δ subunits are encoded in mammals by four genes, CACNA2D1-4. They play important roles in trafficking and function of the CaV channel complexes. Here we report biallelic variants in CACNA2D1, encoding the α2δ-1 protein, in two unrelated individuals showing a developmental and epileptic encephalopathy. Patient 1 has a homozygous frameshift variant c.818_821dup/p.(Ser275Asnfs*13) resulting in nonsense-mediated mRNA decay of the CACNA2D1 transcripts, and absence of α2δ-1 protein detected in patient-derived fibroblasts. Patient 2 is compound heterozygous for an early frameshift variant c.13_23dup/p.(Leu9Alafs*5), highly probably representing a null allele and a missense variant c.626G>A/p.(Gly209Asp). Our functional studies show that this amino-acid change severely impairs the function of α2δ-1 as a calcium channel subunit, with strongly reduced trafficking of α2δ-1G209D to the cell surface and a complete inability of α2δ-1G209D to increase the trafficking and function of CaV2 channels. Thus, biallelic loss-of-function variants in CACNA2D1 underlie the severe neurodevelopmental disorder in these two patients. Our results demonstrate the critical importance and non-interchangeability of α2δ-1 and other α2δ proteins for normal human neuronal development.
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