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

Autor: Sanchis-Juan A; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK., Hasenahuer MA; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK., Baker JA; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., McTague A; Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK., Barwick K; Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK., Kurian MA; Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, UK., Duarte ST; Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, Lisbon, Portugal., Carss KJ; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK., Thornton J; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Raymond FL; NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2020 Jul; Vol. 8 (7), pp. e1106. Date of Electronic Publication: 2020 Apr 29.
DOI: 10.1002/mgg3.1106
Abstrakt: 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.
(© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
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