Biallelic CACNA2D1 loss-of-function variants cause early-onset developmental epileptic encephalopathy.

Autor: Dahimene S; Department of Neuroscience Physiology and Pharmacology, University College London (UCL), London WC1E 6BT, UK., von Elsner L; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Holling T; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Mattas LS; Neurology and Neurological Sciences, Pediatrics, Division of Medical Genetics, Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA 94304, USA., Pickard J; Department of Neuroscience Physiology and Pharmacology, University College London (UCL), London WC1E 6BT, UK., Lessel D; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Pilch KS; Department of Neuroscience Physiology and Pharmacology, University College London (UCL), London WC1E 6BT, UK., Kadurin I; Department of Neuroscience Physiology and Pharmacology, University College London (UCL), London WC1E 6BT, UK., Pratt WS; Department of Neuroscience Physiology and Pharmacology, University College London (UCL), London WC1E 6BT, UK., Zhulin IB; Department of Microbiology and Translational Data Analytics Institute, The Ohio State University, Columbus, OH, 43210, USA., Dai H; Department of Molecular and Human Genetics, Baylor College of Medicine/NGS-Molecular, Baylor Genetics, Houston, TX, USA., Hempel M; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Ruzhnikov MRZ; Neurology and Neurological Sciences, Pediatrics, Division of Medical Genetics, Stanford University and Lucile Packard Children's Hospital, Palo Alto, CA 94304, USA., Kutsche K; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Dolphin AC; Department of Neuroscience Physiology and Pharmacology, University College London (UCL), London WC1E 6BT, UK.
Jazyk: angličtina
Zdroj: Brain : a journal of neurology [Brain] 2022 Aug 27; Vol. 145 (8), pp. 2721-2729.
DOI: 10.1093/brain/awac081
Abstrakt: 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.
(© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze: MEDLINE
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