Current knowledge of SLC6A1-related neurodevelopmental disorders.

Autor:	Goodspeed K; Children's Health, Medical Center, UT Southwestern, Dallas, TX 75235, USA.; Department of Pediatrics, Medical Center, UT Southwestern, Dallas, TX 75235, USA., Pérez-Palma E; Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44195, USA., Iqbal S; Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA 02142, USA.; Broad Institute of MIT and Harvard, Center for Development of Therapeutics, Cambridge, MA 02142, USA., Cooper D; Children's Health, Medical Center, UT Southwestern, Dallas, TX 75235, USA., Scimemi A; Department of Biological Sciences, University at Albany, Albany, NY 12222, USA., Johannesen KM; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia, Dianalund 4293, Denmark.; Department of Regional Health Research, Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark., Stefanski A; Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44195, USA., Demarest S; Departments of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO, USA.; Department of Pediatric Neurology and Neuroscience Institute, Children's Hospital Colorado, Aurora, CO, USA., Helbig KL; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Kang J; Department of Neurology, Vanderbilt University Medical Center, TN 37232, USA., Shaffo FC; Department of Pediatrics, Medical Center, UT Southwestern, Dallas, TX 75235, USA., Prentice B; SLC6A1 Connect Foundation, Denver, CO 80210, USA., Brownstein CA; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Lim B; Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea., Helbig I; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., De Los Reyes E; Department of Pediatric Neurology, Nationwide Children's Hospital, Columbus, OH, USA.; The Ohio State University College of Medicine, Columbus, OH, USA., McKnight D; GeneDx, Gaithersburg, MD 20877, USA., Crunelli V; Neuroscience Division, School of Bioscience, Cardiff University, Cardiff, UK.; Faculty of Medicine and Surgery, Malta University, Msida, Malta., Campbell AJ; Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA 02142, USA.; Broad Institute of MIT and Harvard, Center for Development of Therapeutics, Cambridge, MA 02142, USA., Møller RS; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Center Filadelfia, Dianalund 4293, Denmark.; Department of Regional Health Research, Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark., Freed A; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Lal D; Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH 44195, USA.; Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA 02142, USA.; Neurological Institute, Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2020 Oct 13; Vol. 2 (2), pp. fcaa170. Date of Electronic Publication: 2020 Oct 13 (Print Publication: 2020).
DOI:	10.1093/braincomms/fcaa170
Abstrakt:	Advances in gene discovery have identified genetic variants in the solute carrier family 6 member 1 gene as a monogenic cause of neurodevelopmental disorders, including epilepsy with myoclonic atonic seizures, autism spectrum disorder and intellectual disability. The solute carrier family 6 member 1 gene encodes for the GABA transporter protein type 1, which is responsible for the reuptake of the neurotransmitter GABA, the primary inhibitory neurotransmitter in the central nervous system, from the extracellular space. GABAergic inhibition is essential to counterbalance neuronal excitation, and when significantly disrupted, it negatively impacts brain development leading to developmental differences and seizures. Aggregation of patient variants and observed clinical manifestations expand understanding of the genotypic and phenotypic spectrum of this disorder. Here, we assess genetic and phenotypic features in 116 individuals with solute carrier family 6 member 1 variants, the vast majority of which are likely to lead to GABA transporter protein type 1 loss-of-function. The knowledge acquired will guide therapeutic decisions and the development of targeted therapies that selectively enhance transporter function and may improve symptoms. We analysed the longitudinal and cell type-specific expression of solute carrier family 6 member 1 in humans and localization of patient and control missense variants in a novel GABA transporter protein type 1 protein structure model. In this update, we discuss the progress made in understanding and treating solute carrier family 6 member 1-related disorders thus far, through the concerted efforts of clinicians, scientists and family support groups. (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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