Dahimene, Shehrazade;
von Elsner, Leonie;
Holling, Tess;
Mattas, Lauren S;
Pickard, Jess;
Lessel, Davor;
Pilch, Kjara S;
... Dolphin, Annette C; + view all
(2022)
Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.
Brain
10.1093/brain/awac081.
(In press).
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Abstract
Voltage-gated calcium (CaV) channels form three sub-families (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 (DEE). 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 likely 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.
| Type: | Article |
|---|---|
| Title: | Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awac081 |
| Publisher version: | https://doi.org/10.1093/brain/awac081 |
| Language: | English |
| Additional information: | Copyright © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | epileptic encephalopathy, calcium channel, loss-of-function, biallelic variants, CACNA2D1 |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10145668 |
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