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J Med Genet 50:118-123 doi:10.1136/jmedgenet-2012-101223
  • New loci
  • Original article

Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy

  1. Orly Elpeleg1
  1. 1The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
  2. 2The Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel
  3. 3The Specialist Clinics Jenin, Primary Health Care, Ministry of Health, Jenin, Palestine
  4. 4Palestine Medical Complex, Ramallah, Palestine
  1. Correspondence to Professor Orly Elpeleg, The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel; Elpeleg{at}hadassah.org.il and Professor Nathan Dascal, The Department of Physiology and Pharmacology, Sackler School of Medicine Tel Aviv University Ramat Aviv, Tel Aviv 69978, Israel; dascaln{at}post.tau.ac.il
  • Received 7 August 2012
  • Revised 29 November 2012
  • Accepted 29 November 2012

Abstract

Background Early infantile epileptic encephalopathies usually manifest as severely impaired cognitive and motor development and often result in a devastating permanent global developmental delay and intellectual disability. A large set of genes has been implicated in the aetiology of this heterogeneous group of disorders. Among these, the ion channelopathies play a prominent role. In this study, we investigated the genetic cause of infantile epilepsy in three affected siblings.

Methods and results Homozygosity mapping in DNA samples followed by exome analysis in one of the patients resulted in the identification of a homozygous mutation, p.L1040P, in the CACNA2D2 gene. This gene encodes the auxiliary α2δ2 subunit of high voltage gated calcium channels. The expression of the α2δ2-L1040P mutant instead of α2δ2 wild-type (WT) in Xenopus laevis oocytes was associated with a notable reduction of current density of both N (CaV2.2) and L (CaV1.2) type calcium channels. Western blot and confocal imaging analyses showed that the α2δ2-L1040P mutant was synthesised normally in oocyte but only the α2δ2-WT, and not the α2δ2-L1040P mutant, increased the expression of α1B, the pore forming subunit of CaV2.2, at the plasma membrane. The expression of α2δ2-WT with CaV2.2 increased the surface expression of α1B 2.5–3 fold and accelerated current inactivation, whereas α2δ2-L1040P did not produce any of these effects.

Conclusions L1040P mutation in the CACNA2D2 gene is associated with dysfunction of α2δ2, resulting in reduced current density and slow inactivation in neuronal calcium channels. The prolonged calcium entry during depolarisation and changes in surface density of calcium channels caused by deficient α2δ2 could underlie the epileptic phenotype. This is the first report of an encephalopathy caused by mutation in the auxiliary α2δ subunit of high voltage gated calcium channels in humans, illustrating the importance of this subunit in normal physiology of the human brain.