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A Novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy

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.

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DOI: 10.1371/journal.pone.0082154

Abstract

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.

Item Type:Article
ID Code:9560
Status:Published
Refereed:Yes
Uncontrolled Keywords:Epileptic encephalopathy (EE), CACNA2D2 mutations, CELSR3
Subjects:Area 06 - Scienze mediche > MED/03 Genetica medica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Scienze Biomediche
002 Altri enti e centri di ricerca del Nord Sardegna > CRS4 Center for Advanced Studies, Research and Development in Sardinia, Pula
Publisher:Public Library of Science
eISSN:1932-6203
Copyright Holders:© 2013 Pippucci et al.
Deposited On:08 Jan 2014 10:01

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