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

Cristina Elena Niturad, Dorit Lev, Vera M. Kalscheuer, Agnieszka Charzewska, Julian Schubert, Tally Lerman-Sagie, Hester Y. Kroes, Renske Oegema, Monica Traverso, Nicola Specchio, Maria Lassota, Jamel Chelly, Odeya Bennett-Back, Nirit Carmi, Tal Koffler-Brill, Michele Iacomino, Marina Trivisano, Giuseppe Capovilla, Pasquale Striano, Magdalena NawaraSylwia Rzoca, Ute Fischer, Melanie Bienek, Corinna Jensen, Hao Hu, Holger Thiele, Janine Altmüller, Roland Krause, Patrick May, Felicitas Becker, Rudi Balling, Saskia Biskup, Stefan A. Haas, Peter Nürnberg, Koen L.I. Van Gassen, Holger Lerche, Federico Zara, Snezana Maljevic, Esther Leshinsky-Silver

Research output: Contribution to journalArticle

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 GABA A 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 α 3 -subunit of the GABA A 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 NH 2 -terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α 3 -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.

Original languageEnglish
Pages (from-to)2879-2894
Number of pages16
JournalBrain
Volume140
Issue number11
DOIs
Publication statusPublished - Nov 1 2017

Fingerprint

Brain Diseases
Epilepsy
Genes
Mutation
GABA-A Receptors
Phenotype
Intellectual Disability
gamma-Aminobutyric Acid
X Chromosome Inactivation
Inheritance Patterns
X-Linked Genes
Penetrance
Xenopus laevis
Pedigree
Ion Channels
Oocytes
Anions
Fibroblasts
Chromosomes

Keywords

  • epilepsy
  • intellectual disability
  • neuronal inhibition
  • X-linked disease

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

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

Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. / Niturad, Cristina Elena; 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; Rzoca, Sylwia; Fischer, Ute; Bienek, Melanie; Jensen, Corinna; Hu, Hao; Thiele, Holger; Altmüller, Janine; Krause, Roland; May, Patrick; Becker, Felicitas; Balling, Rudi; Biskup, Saskia; Haas, Stefan A.; Nürnberg, Peter; Van Gassen, Koen L.I.; Lerche, Holger; Zara, Federico; Maljevic, Snezana; Leshinsky-Silver, Esther.

In: Brain, Vol. 140, No. 11, 01.11.2017, p. 2879-2894.

Research output: Contribution to journalArticle

Niturad, CE, Lev, D, Kalscheuer, VM, Charzewska, A, Schubert, J, Lerman-Sagie, T, Kroes, HY, Oegema, R, Traverso, M, Specchio, N, Lassota, M, Chelly, J, Bennett-Back, O, Carmi, N, Koffler-Brill, T, Iacomino, M, Trivisano, M, Capovilla, G, Striano, P, Nawara, M, Rzoca, S, Fischer, U, Bienek, M, Jensen, C, Hu, H, Thiele, H, Altmüller, J, Krause, R, May, P, Becker, F, Balling, R, Biskup, S, Haas, SA, Nürnberg, P, Van Gassen, KLI, Lerche, H, Zara, F, Maljevic, S & Leshinsky-Silver, E 2017, 'Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features', Brain, vol. 140, no. 11, pp. 2879-2894. https://doi.org/10.1093/brain/awx236
Niturad CE, Lev D, Kalscheuer VM, Charzewska A, Schubert J, Lerman-Sagie T et al. Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain. 2017 Nov 1;140(11):2879-2894. https://doi.org/10.1093/brain/awx236
Niturad, Cristina Elena ; 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 ; Rzoca, Sylwia ; Fischer, Ute ; Bienek, Melanie ; Jensen, Corinna ; Hu, Hao ; Thiele, Holger ; Altmüller, Janine ; Krause, Roland ; May, Patrick ; Becker, Felicitas ; Balling, Rudi ; Biskup, Saskia ; Haas, Stefan A. ; Nürnberg, Peter ; Van Gassen, Koen L.I. ; Lerche, Holger ; Zara, Federico ; Maljevic, Snezana ; Leshinsky-Silver, Esther. / Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. In: Brain. 2017 ; Vol. 140, No. 11. pp. 2879-2894.
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AU - Lev, Dorit

AU - Kalscheuer, Vera M.

AU - Charzewska, Agnieszka

AU - Schubert, Julian

AU - Lerman-Sagie, Tally

AU - Kroes, Hester Y.

AU - Oegema, Renske

AU - Traverso, Monica

AU - Specchio, Nicola

AU - Lassota, Maria

AU - Chelly, Jamel

AU - Bennett-Back, Odeya

AU - Carmi, Nirit

AU - Koffler-Brill, Tal

AU - Iacomino, Michele

AU - Trivisano, Marina

AU - Capovilla, Giuseppe

AU - Striano, Pasquale

AU - Nawara, Magdalena

AU - Rzoca, Sylwia

AU - Fischer, Ute

AU - Bienek, Melanie

AU - Jensen, Corinna

AU - Hu, Hao

AU - Thiele, Holger

AU - Altmüller, Janine

AU - Krause, Roland

AU - May, Patrick

AU - Becker, Felicitas

AU - Balling, Rudi

AU - Biskup, Saskia

AU - Haas, Stefan A.

AU - Nürnberg, Peter

AU - Van Gassen, Koen L.I.

AU - Lerche, Holger

AU - Zara, Federico

AU - Maljevic, Snezana

AU - Leshinsky-Silver, Esther

PY - 2017/11/1

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N2 - 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 GABA A 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 α 3 -subunit of the GABA A 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 NH 2 -terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α 3 -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.

AB - 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 GABA A 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 α 3 -subunit of the GABA A 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 NH 2 -terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α 3 -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.

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