Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants.

Autor:	Allen JP; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States.; Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States., Garber KB; Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta GA 30322, United States.; EGL Genetics, 2460 Mountain Industrial Blvd., Tucker, GA 30084, United States., Perszyk R; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States., Khayat CT; Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA 30332, United States., Kell SA; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States.; Department of Chemistry, Emory University School of Medicine, 1515 Dickey Dr, Atlanta, GA 30322, United States., Kaneko M; Division of Genomic Medicine, Department of Pathology, Children's Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, United States.; Center for Personalized Medicine, Children's Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, United States., Quindipan C; Center for Personalized Medicine, Children's Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, United States., Saitta S; Division of Clinical Genetics, Departments of Human Genetics, OBGYN and Pediatrics, David Geffen School of Medicine at UCLA, 200 Medical Plaza, Los Angeles, CA 90095, United States., Ladda RL; Division of Human Genetics, Department of Pediatrics, Penn State College of Medicine, 600 University Dr, Hershey, PA 17033, United States., Hewson S; Department of Genetic Counselling, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5G 1X8, Canada., Inbar-Feigenberg M; Division of Clinical & Metabolic Genetics, The Hospital for Sick Children and Pediatrics, University of Toronto, 555 University Avenue, Toronto ON M5G 1X8, Canada., Prasad C; Department of Pediatrics (Section of Genetics and Metabolism), Western University and Schulich School of Medicine and Dentistry, Children's Hospital LHSC, 800 Commissioners Road East, London, ON N6A5W9, Canada., Prasad AN; Division of Pediatric Neurology, Department of Pediatrics and Clinical Neurological Sciences, Western University and Schulich School of Medicine and Dentistry, Children's Hospital LHSC, 800 Commissioners Road East, London, ON N6A5W9, Canada., Olewiler L; Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216, United States., Mu W; Department of Genetic Medicine, Johns Hopkins University, 600 N. Wolfe St., Baltimore MD 21287, United States., Rosenthal LS; Department of Neurology, Johns Hopkins University, 601 N. Caroline St., Baltimore MD 21287, United States., Scala M; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Largo Paolo Daneo, 3, 16132 Genova GE, Italy.; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Pavilion 16, Via Gerolamo Gaslini, 516147 Genoa GE, Italy., Striano P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Largo Paolo Daneo, 3, 16132 Genova GE, Italy.; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Pavilion 16, Via Gerolamo Gaslini, 516147 Genoa GE, Italy., Zara F; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Pavilion 20, Via Gerolamo Gaslini, 516147 Genoa GE, Italy., McCullock TW; Department Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester NY, 14642, United States., Jauss RT; Institute of Human Genetics, University of Leipzig Medical Center, Philipp-Rosenthal-Str. 55, Haus W, Leipzig 04103, Germany., Lemke JR; Institute of Human Genetics, University of Leipzig Medical Center, Philipp-Rosenthal-Str. 55, Haus W, Leipzig 04103, Germany., MacLean DM; Department Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester NY, 14642, United States., Zhu C; Department of Biomedical Engineering, Georgia Institute of Technology, 313 Ferst Drive, Atlanta, GA 30332, United States., Yuan H; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States.; Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States., Myers SJ; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States.; Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States., Traynelis SF; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States.; Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322, United States.; Emory Neurodegenerative Disease Center, 615 Michael St., Emory University School of Medicine, Atlanta, GA 30322, United States.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2024 Feb 01; Vol. 33 (4), pp. 355-373.
DOI:	10.1093/hmg/ddad188
Abstrakt:	GRID1 and GRID2 encode the enigmatic GluD1 and GluD2 proteins, which form tetrameric receptors that play important roles in synapse organization and development of the central nervous system. Variation in these genes has been implicated in neurodevelopmental phenotypes. We evaluated GRID1 and GRID2 human variants from the literature, ClinVar, and clinical laboratories and found that many of these variants reside in intolerant domains, including the amino terminal domain of both GRID1 and GRID2. Other conserved regions, such as the M3 transmembrane domain, show different intolerance between GRID1 and GRID2. We introduced these variants into GluD1 and GluD2 cDNA and performed electrophysiological and biochemical assays to investigate the mechanisms of dysfunction of GRID1/2 variants. One variant in the GRID1 distal amino terminal domain resides at a position predicted to interact with Cbln2/Cbln4, and the variant disrupts complex formation between GluD1 and Cbln2, which could perturb its role in synapse organization. We also discovered that, like the lurcher mutation (GluD2-A654T), other rare variants in the GRID2 M3 domain create constitutively active receptors that share similar pathogenic phenotypes. We also found that the SCHEMA schizophrenia M3 variant GluD1-A650T produced constitutively active receptors. We tested a variety of compounds for their ability to inhibit constitutive currents of GluD receptor variants and found that pentamidine potently inhibited GluD2-T649A constitutive channels (IC50 50 nM). These results identify regions of intolerance to variation in the GRID genes, illustrate the functional consequences of GRID1 and GRID2 variants, and suggest how these receptors function normally and in disease. (© The Author(s) 2023. Published by Oxford University Press.)
Databáze:	MEDLINE
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