title: Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy.
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.
  
  
  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 α(2)δ2 subunit of high voltage gated calcium channels. The expression of the α(2)δ2-L1040P mutant instead of α(2)δ2 wild-type (WT) in Xenopus laevis oocytes was associated with a notable reduction of current density of both N (Ca(V)2.2) and L (Ca(V)1.2) type calcium channels. Western blot and confocal imaging analyses showed that the α(2)δ2-L1040P mutant was synthesised normally in oocyte but only the α(2)δ2-WT, and not the α(2)δ2-L1040P mutant, increased the expression of α(1B), the pore forming subunit of Ca(V)2.2, at the plasma membrane. The expression of α(2)δ2-WT with Ca(V)2.2 increased the surface expression of α(1B) 2.5-3 fold and accelerated current inactivation, whereas α(2)δ2-L1040P did not produce any of these effects.
  
  
  CONCLUSIONS
  L1040P mutation in the CACNA2D2 gene is associated with dysfunction of α(2)δ2, 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 α(2)δ2 could underlie the epileptic phenotype. This is the first report of an encephalopathy caused by mutation in the auxiliary α(2)δ subunit of high voltage gated calcium channels in humans, illustrating the importance of this subunit in normal physiology of the human brain.
authors: The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Simon
authors: S
authors: Edvardson
authors: Shimrit
authors: S
authors: Oz
authors: Fida Aziz
authors: FA
authors: Abulhijaa
authors: Flora Barghouthi
authors: FB
authors: Taher
authors: Avraham
authors: A
authors: Shaag
authors: Shamir
authors: S
authors: Zenvirt
authors: Nathan
authors: N
authors: Dascal
authors: Orly
authors: O
authors: Elpeleg
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D053447:Channelopathies / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009865:Oocytes; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: C480968:CACNA2D2 protein, human; D015220:Calcium Channels; D011994:Recombinant Proteins