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Typically, these variants cause a loss-of-function molecular phenotype whereby \u03b3-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits \u03b3-aminobutyric acid transaminase to increase tonic \u03b3-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different \u03b3-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic \u03b3-aminobutyric acid A receptor construct, to resemble the \u03b3-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of \u03b3-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of \u03b3-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa162","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T00:05:59Z","timestamp":1604534759000},"source":"Crossref","is-referenced-by-count":42,"title":["Gain-of-function\n                    <i>GABRB3<\/i>\n                    variants identified in vigabatrin-hypersensitive epileptic encephalopathies"],"prefix":"10.1093","volume":"2","author":[{"given":"Nathan L","family":"Absalom","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Health, School of Pharmacy, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian W Y","family":"Liao","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health, School of Pharmacy, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavitha","family":"Kothur","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre at The Children\u2019s Hospital at Westmead, Westmead, New South Wales 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh C","family":"Indurthi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health, School of Pharmacy, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Bennetts","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, The Children\u2019s Hospital at Westmead, Westmead, New South Wales 2145, Australia"},{"name":"Discipline of Paediatrics and Adolescent Health, The Children's Hospital at Westmead Clinical School, The University of Sydney, 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Troedson","sequence":"additional","affiliation":[{"name":"T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1219-4781","authenticated-orcid":false,"given":"Shekeeb S","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre at The Children\u2019s Hospital at Westmead, Westmead, New South Wales 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Gupta","sequence":"additional","affiliation":[{"name":"T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain S","family":"McGregor","sequence":"additional","affiliation":[{"name":"Faculty of Science, Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T","family":"Bowen","sequence":"additional","affiliation":[{"name":"Faculty of Science, Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Lederer","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Genetics, Center for Human Genetics, Gosselies 6041, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Mary","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Genetics, Center for Human Genetics, Gosselies 6041, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesbeth","family":"De Waele","sequence":"additional","affiliation":[{"name":"Department of Development and Regeneration, KULeuven, Leuven 3000, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Development and Regeneration, KULeuven, Leuven 3000, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Gill","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre at The Children\u2019s Hospital at Westmead, Westmead, New South Wales 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manju A","family":"Kurian","sequence":"additional","affiliation":[{"name":"Molecular Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1E 6BT, UK"},{"name":"Department of Neurology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"McTague","sequence":"additional","affiliation":[{"name":"Molecular Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1E 6BT, UK"},{"name":"Department of Neurology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikke S","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund 4293, Denmark"},{"name":"Department of Regional Health Research, University of Southern Denmark, Odense 5230, 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