Article (Scientific journals)
Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features
Niturad, Elena Christina; Lev, Dorit; Kalscheuer, Vera M et al.
2017In Brain: a Journal of Neurology, 140 (11), p. 2879-2894
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Keywords :
Epilepsy; GABRA3; Seizures; X-linked disease; intellectual disability; neuronal inhibition
Abstract :
[en] Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Niturad, Elena Christina
Lev, Dorit
Kalscheuer, Vera M
Charzewska, Agnieszka
Schubert, Julian
Lerman-Sagie, Tally
Kroes, Hester Y
Oegema, Renske
Traverso, Monica
Specchio, Nicola
Lassota, Maria
Chelly, Jamel
Bennett-Back, Odeya
Carmi, Nirit
Koffler-Brill, Tal
Iacomino, Michele
Trivisano, Marina
Capovilla, Giuseppe
Striano, Pasquale
Nawara, Magdalena
Rzonca, Sylwia
Fischer, Ute
Bienek, Melanie
Jensen, Corinna
Hu, Hao
Thiele, Holger
Altmüller, Janine
Krause, Roland  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Becker, Felicitas
EuroEPINOMICS Consortium
Balling, Rudi ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Biskup, Saskia
Haas, Stefan A
Nürnberg, Peter
van Gassen, Koen L I
Lerche, Holger
Zara, Federico
Maljevic, Snezana
Leshinsky-Silver, Esther
More authors (30 more) Less
External co-authors :
yes
Language :
English
Title :
Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features
Publication date :
01 November 2017
Journal title :
Brain: a Journal of Neurology
ISSN :
1460-2156
Publisher :
Oxford University Press, Oxford, United Kingdom
Volume :
140
Issue :
11
Pages :
2879-2894
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 09 October 2017

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