Author(s):
Sanchis-Juan, A ; Hasenahuer, MA ; Baker, JA ; McTague, A ; Barwick, K ; Kurian, MA ; Duarte, ST ; Carss, KJ ; Thornton, J ; Raymond, FL
Date: 2020
Persistent ID: http://hdl.handle.net/10400.17/3708
Origin: Repositório do Centro Hospitalar de Lisboa Central, EPE
Subject(s): Child; Epilepsy; Female; Humans; Language Disorders; Molecular Dynamics Simulation; Protein Domains; Protein Multimerization; Receptors, GABA-A; Stereotyped Behavior; Ion Channel Gating; Mutation, Missense; HDE NEU PEd
Description
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.
