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

  • Shehrazade Dahimene
  • Leonie von Elsner
  • Tess Holling
  • Lauren S Mattas
  • Jess Pickard
  • Davor Lessel
  • Kjara S Pilch
  • Ivan Kadurin
  • Wendy S Pratt
  • Igor B Zhulin
  • Hongzheng Dai
  • Maja Hempel
  • Maura R Z Ruzhnikov
  • Kerstin Kutsche (Geteilte/r Letztautor/in)
  • Annette C Dolphin (Geteilte/r Letztautor/in)

Beteiligte Einrichtungen

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.

Bibliografische Daten

OriginalspracheEnglisch
ISSN0006-8950
DOIs
StatusVeröffentlicht - 27.08.2022

Anmerkungen des Dekanats

© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.

PubMed 35293990