Pippucci, Tommaso and Parmeggiani, Antonia and Palombo, Flavia and Maresca, Alessandra and Angius, Andrea and Crisponi, Laura and Cucca, Francesco and Liguori, Rocco and Valentino, Maria Lucia and Seri, Marco and Carelli, Valerio (2013) A Novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. PLoS One, Vol. 8 (12), e82154. eISSN 1932-6203. Article.
Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental.
I documenti depositati in UnissResearch sono protetti dalle leggi che regolano il diritto d'autore
Repository Staff Only: item control page