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  Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features

Niturad, C. E., Lev, D., Kalscheuer, V. M., Charzewska, A., Schubert, J., Lerman-Sagie, T., et al. (2017). Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain, 140(11), 2879-2894. doi:10.1093/brain/awx236.

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© The Author (2017)




Niturad, C. E., Author
Lev, D., Author
Kalscheuer, V. M.1, Author              
Charzewska, A., Author
Schubert, J., Author
Lerman-Sagie, T., Author
Kroes, H. Y., Author
Oegema, R., Author
Traverso, M., Author
Specchio, N., Author
Lassota, M., Author
Chelly, J., Author
Bennett-Back, O., Author
Carmi, N., Author
Koffler-Brill, T., Author
Iacomino, M., Author
Trivisano, M., Author
Capovilla, G., Author
Striano, P., Author
Nawara, M., Author
Rzonca, S., AuthorFischer, U.2, Author              Bienek, M., AuthorJensen, C., AuthorHu, H., AuthorThiele, H., AuthorAltmüller, J., AuthorKrause, R., AuthorMay, P., AuthorBecker, F., AuthorEuro, Epinomics Consortium, AuthorBalling, R., AuthorBiskup, S., AuthorHaas, S. A.3, Author              Nürnberg, P., Authorvan Gassen, K. L. I., AuthorLerche, H., AuthorZara, F., AuthorMaljevic, S., AuthorLeshinsky-Silver, E., Author more..
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              
2Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
3Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              


Free keywords: Adolescent Adult Animals Brain Diseases/*genetics Child Child, Preschool Cleft Palate/*genetics Developmental Disabilities/*genetics Epilepsy/*genetics *Facies Female Genetic Variation Humans Intellectual Disability/*genetics Male Microcephaly/genetics Mutagenesis, Site-Directed Nystagmus, Pathologic/*genetics Oocytes/metabolism Patch-Clamp Techniques Pedigree Receptors, GABA-A/*genetics/metabolism Syndrome Xenopus laevis Young Adult gamma-Aminobutyric Acid/metabolism X-linked disease epilepsy intellectual disability neuronal inhibition
 Abstract: 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 alpha3-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 alpha3-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.


Language(s): eng - English
 Dates: 2017-10-072017-11-01
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1093/brain/awx236
ISSN: 1460-2156 (Electronic)0006-8950 (Print)
 Degree: -



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Title: Brain
  Other : Brain
Source Genre: Journal
Publ. Info: Oxford : Oxford University Press
Pages: - Volume / Issue: 140 (11) Sequence Number: - Start / End Page: 2879 - 2894 Identifier: -