Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy
Simon Edvardson1, Shimrit Oz, Fida Aziz Abulhijaa
1The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Insights
A CACNA2D2 gene mutation causes infantile epilepsy by disrupting neuronal calcium channel function. This study identifies a novel genetic cause for early infantile epileptic encephalopathy, highlighting the role of auxiliary calcium channel subunits.
Area of Science:
- Neurogenetics
- Ion Channel Physiology
- Molecular Neuroscience
Background:
- Early infantile epileptic encephalopathies (EIEE) are severe developmental disorders often linked to genetic mutations.
- Ion channelopathies, particularly those affecting calcium channels, are significant contributors to EIEE.
- Investigating genetic causes in affected siblings is crucial for understanding EIEE pathogenesis.
Observation:
- A homozygous mutation (p.L1040P) in the CACNA2D2 gene was identified in three siblings with infantile epilepsy.
- The CACNA2D2 gene encodes the auxiliary α(2)δ2 subunit of high voltage-gated calcium channels.
- The identified mutation affects the function and expression of specific calcium channel subtypes.
Findings:
- The p.L1040P mutation in CACNA2D2 leads to reduced current density and impaired inactivation of neuronal calcium channels (Ca(V)2.2 and Ca(V)1.2).
- Mutant α(2)δ2-L1040P does not facilitate the plasma membrane expression of the Ca(V)2.2 α(1B) subunit, unlike wild-type α(2)δ2.
- This dysfunction in calcium channel regulation is directly linked to the observed epileptic phenotype.
Implications:
- This is the first report of an encephalopathy caused by a mutation in the auxiliary α(2)δ subunit of human high voltage-gated calcium channels.
- The findings underscore the critical role of the α(2)δ2 subunit in human brain physiology and neuronal excitability.
- Understanding these molecular mechanisms opens new avenues for diagnosing and potentially treating infantile epilepsy.
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 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.
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