A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy.
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 a...
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2013
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oai:doaj.org-article:aecdf351c8ad4206b5d7427262e5fb7b2021-11-18T08:41:51ZA novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy.1932-620310.1371/journal.pone.0082154https://doaj.org/article/aecdf351c8ad4206b5d7427262e5fb7b2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24358150/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Contribution 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.Tommaso PippucciAntonia ParmeggianiFlavia PalomboAlessandra MarescaAndrea AngiusAndrea AngiusLaura CrisponiFrancesco CuccaRocco LiguoriMaria Lucia ValentinoMarco SeriValerio CarelliPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e82154 (2013) |
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Medicine R Science Q Tommaso Pippucci Antonia Parmeggiani Flavia Palombo Alessandra Maresca Andrea Angius Andrea Angius Laura Crisponi Francesco Cucca Rocco Liguori Maria Lucia Valentino Marco Seri Valerio Carelli A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. |
| description |
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. |
| format |
article |
| author |
Tommaso Pippucci Antonia Parmeggiani Flavia Palombo Alessandra Maresca Andrea Angius Andrea Angius Laura Crisponi Francesco Cucca Rocco Liguori Maria Lucia Valentino Marco Seri Valerio Carelli |
| author_facet |
Tommaso Pippucci Antonia Parmeggiani Flavia Palombo Alessandra Maresca Andrea Angius Andrea Angius Laura Crisponi Francesco Cucca Rocco Liguori Maria Lucia Valentino Marco Seri Valerio Carelli |
| author_sort |
Tommaso Pippucci |
| title |
A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. |
| title_short |
A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. |
| title_full |
A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. |
| title_fullStr |
A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. |
| title_full_unstemmed |
A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. |
| title_sort |
novel null homozygous mutation confirms cacna2d2 as a gene mutated in epileptic encephalopathy. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/aecdf351c8ad4206b5d7427262e5fb7b |
| work_keys_str_mv |
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