Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate

• Published in: Molecular genetics & genomic medicine 2020-07, Vol.8 (7), p.e1106-n/a
• Main Authors: Sanchis‐Juan, Alba, Hasenahuer, Marcia A., Baker, James A., McTague, Amy, Barwick, Katy, Kurian, Manju A., Duarte, Sofia T., Carss, Keren J., Thornton, Janet, Raymond, F. Lucy
• Format: Article
• Language: English
• Subjects: Child; Cys‐loop receptor; Desensitization; Encephalopathy; Epilepsy; Epilepsy - genetics; Epilepsy - pathology; epileptic encephalopathy; Equivalence; Excitability; Female; GABRA2; Gene sequencing; Genes; Genomes; Helices; Humans; Identification methods; Interfaces; Ion Channel Gating; Language Disorders - genetics; Language Disorders - pathology; Ligands; Missense mutation; Molecular Dynamics Simulation; Mutation; Mutation, Missense; Neurological diseases; Original; Population control; Population studies; Protein Domains; Protein Multimerization; protein structural analysis; Proteins; Receptors; Receptors, GABA-A - chemistry; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Stereotyped Behavior; Structural analysis; Whole genome sequencing
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1106

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. This 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.