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Structural Analysis of Pathogenic Missense Mutations in GABRA2 and Identification of a Novel de Novo Variant in the Desensitization Gate

2020Journal article Open access
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dc.contributor.authorSanchis-Juan, A
dc.contributor.authorHasenahuer, MA
dc.contributor.authorBaker, JA
dc.contributor.authorMcTague, A
dc.contributor.authorBarwick, K
dc.contributor.authorKurian, MA
dc.contributor.authorDuarte, ST
dc.contributor.authorCarss, KJ
dc.contributor.authorThornton, J
dc.contributor.authorRaymond, FL
dc.date.accessioned2021-05-27T08:18:02Z
dc.date.available2021-05-27T08:18:02Z
dc.date.issued2020
dc.description.abstractBackground: Cys-loop receptors control neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six missense variants in GABRA2, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE). We identified a novel de novo missense variant in GABRA2 in a patient with EIEE and performed protein structural analysis of the seven variants. Methods: The novel variant was identified by trio whole-genome sequencing. We performed protein structural analysis of the seven variants, and compared them to previously reported pathogenic mutations at equivalent positions in other Cys-loop receptors. Additionally, we studied the distribution of disease-associated variants in the transmembrane helices of these proteins. Results: The seven variants are in the transmembrane domain, either close to the desensitization gate, the activation gate, or in inter-subunit interfaces. Six of them have pathogenic mutations at equivalent positions in other Cys-loop receptors, emphasizing the importance of these residues. Also, pathogenic mutations are more common in the pore-lining helix, consistent with this region being highly constrained for variation in control populations. Conclusion: Our study reports a novel pathogenic variant in GABRA2, characterizes the regions where pathogenic mutations are in the transmembrane helices, and underscores the value of considering sequence, evolutionary, and structural information as a strategy for variant interpretation of novel missense mutations.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMol Genet Genomic Med . 2020 Jul;8(7):e1106pt_PT
dc.identifier.doi10.1002/mgg3.1106pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.17/3708
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.subjectChildpt_PT
dc.subjectEpilepsypt_PT
dc.subjectFemalept_PT
dc.subjectHumanspt_PT
dc.subjectLanguage Disorderspt_PT
dc.subjectMolecular Dynamics Simulationpt_PT
dc.subjectProtein Domainspt_PT
dc.subjectProtein Multimerizationpt_PT
dc.subjectReceptors, GABA-Apt_PT
dc.subjectStereotyped Behaviorpt_PT
dc.subjectIon Channel Gatingpt_PT
dc.subjectMutation, Missensept_PT
dc.subjectHDE NEU PEdpt_PT
dc.titleStructural Analysis of Pathogenic Missense Mutations in GABRA2 and Identification of a Novel de Novo Variant in the Desensitization Gatept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue7pt_PT
oaire.citation.startPagee1106pt_PT
oaire.citation.titleMolecular genetics & genomic medicinept_PT
oaire.citation.volume8pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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