Sanchis-Juan, A;
Hasenahuer, MA;
Baker, JA;
McTague, A;
Barwick, K;
Kurian, MA;
Duarte, ST;
... Raymond, FL; + view all
(2020)
Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate.
Molecular Genetics & Genomic Medicine
, Article e1106. 10.1002/mgg3.1106.
(In press).
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Abstract
Background: 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.
| Type: | Article |
|---|---|
| Title: | Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/mgg3.1106 |
| Publisher version: | https://doi.org/10.1002/mgg3.1106 |
| Language: | English |
| Additional information: | Copyright © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Cys‐loop receptor, epileptic encephalopathy, GABRA2, protein structural analysis, whole‐genome sequencing |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10097313 |
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