Niturad, Cristina Elena, Lev, Dorit, Kalscheuer, Vera M., Charzewska, Agnieszka, Schubert, Julian, Lerman-Sagie, Tally, Kroes, Hester Y., Oegema, Renske ORCID: 0000-0002-7146-617X, Traverso, Monica, Specchio, Nicola, Lassota, Maria, Chelly, Jamel, Bennett-Back, Odeya, Carmi, Nirit, Koffler-Brill, Tal, Iacomino, Michele, Trivisano, Marina, Capovilla, Giuseppe, Striano, Pasquale ORCID: 0000-0002-6065-1476, Nawara, Magdalena, Rzonca, Sylwia, Fischer, Ute, Bienek, Melanie, Jensen, Corinna, Hu, Hao, Thiele, Holger, Altmuller, Janine, Krause, Roland ORCID: 0000-0001-9938-7126, May, Patrick ORCID: 0000-0001-8698-3770, Becker, Felicitas, Balling, Rudi ORCID: 0000-0003-2902-5650, Biskup, Saskia, Haas, Stefan A., Nuernberg, Peter, van Gassen, Koen L. I., Lerche, Holger, Zara, Federico ORCID: 0000-0001-9744-5222, Maljevic, Snezana ORCID: 0000-0003-1876-5872 and Leshinsky-Silver, Esther (2017). Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain, 140. S. 2879 - 2895. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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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 alpha(3)-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 a3-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Niturad, Cristina ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lev, DoritUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalscheuer, Vera M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charzewska, AgnieszkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schubert, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerman-Sagie, TallyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroes, Hester Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oegema, RenskeUNSPECIFIEDorcid.org/0000-0002-7146-617XUNSPECIFIED
Traverso, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Specchio, NicolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lassota, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chelly, JamelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bennett-Back, OdeyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carmi, NiritUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koffler-Brill, TalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iacomino, MicheleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trivisano, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Capovilla, GiuseppeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, PasqualeUNSPECIFIEDorcid.org/0000-0002-6065-1476UNSPECIFIED
Nawara, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rzonca, SylwiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bienek, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jensen, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hu, HaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmuller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krause, RolandUNSPECIFIEDorcid.org/0000-0001-9938-7126UNSPECIFIED
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Becker, FelicitasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balling, RudiUNSPECIFIEDorcid.org/0000-0003-2902-5650UNSPECIFIED
Biskup, SaskiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haas, Stefan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Gassen, Koen L. I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zara, FedericoUNSPECIFIEDorcid.org/0000-0001-9744-5222UNSPECIFIED
Maljevic, SnezanaUNSPECIFIEDorcid.org/0000-0003-1876-5872UNSPECIFIED
Leshinsky-Silver, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-213350
DOI: 10.1093/brain/awx236
Journal or Publication Title: Brain
Volume: 140
Page Range: S. 2879 - 2895
Date: 2017
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-NOVO MUTATIONS; OF-FUNCTION MUTATIONS; CHILDHOOD ABSENCE EPILEPSY; GABA(A) RECEPTOR; GENETIC-VARIATION; FEBRILE SEIZURES; DRAVET SYNDROME; FUNCTIONAL PREDICTIONS; PHENOTYPIC SPECTRUM; MYOCLONIC EPILEPSYMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21335

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