Human mutations in SLITRK3 implicated in GABAergic synapse development in mice
This study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental dela...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1222935/full |
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| author | Stephanie Efthymiou Stephanie Efthymiou Wenyan Han Muhammad Ilyas Jun Li Yichao Yu Marcello Scala Marcello Scala Marcello Scala Nancy T. Malintan Muhammad Ilyas Nikoleta Vavouraki Nikoleta Vavouraki Kshitij Mankad Kshitij Mankad Reza Maroofian Clarissa Rocca Vincenzo Salpietro Shenela Lakhani Eric J. Mallack Timothy Blake Palculict Hong Li Guojun Zhang Guojun Zhang Faisal Zafar Nuzhat Rana Noriko Takashima Hayato Matsunaga Claudia Manzoni Pasquale Striano Pasquale Striano Mark F. Lythgoe Jun Aruga Jun Aruga Wei Lu Henry Houlden |
| author_facet | Stephanie Efthymiou Stephanie Efthymiou Wenyan Han Muhammad Ilyas Jun Li Yichao Yu Marcello Scala Marcello Scala Marcello Scala Nancy T. Malintan Muhammad Ilyas Nikoleta Vavouraki Nikoleta Vavouraki Kshitij Mankad Kshitij Mankad Reza Maroofian Clarissa Rocca Vincenzo Salpietro Shenela Lakhani Eric J. Mallack Timothy Blake Palculict Hong Li Guojun Zhang Guojun Zhang Faisal Zafar Nuzhat Rana Noriko Takashima Hayato Matsunaga Claudia Manzoni Pasquale Striano Pasquale Striano Mark F. Lythgoe Jun Aruga Jun Aruga Wei Lu Henry Houlden |
| author_sort | Stephanie Efthymiou |
| collection | DOAJ |
| description | This study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients’ SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3–/–) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function. |
| first_indexed | 2024-03-07T19:10:16Z |
| format | Article |
| id | doaj.art-4c9fba0e92c64e6881b4e82760b9b3c3 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-07T19:10:16Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-4c9fba0e92c64e6881b4e82760b9b3c32024-03-01T04:22:20ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992024-03-011710.3389/fnmol.2024.12229351222935Human mutations in SLITRK3 implicated in GABAergic synapse development in miceStephanie Efthymiou0Stephanie Efthymiou1Wenyan Han2Muhammad Ilyas3Jun Li4Yichao Yu5Marcello Scala6Marcello Scala7Marcello Scala8Nancy T. Malintan9Muhammad Ilyas10Nikoleta Vavouraki11Nikoleta Vavouraki12Kshitij Mankad13Kshitij Mankad14Reza Maroofian15Clarissa Rocca16Vincenzo Salpietro17Shenela Lakhani18Eric J. Mallack19Timothy Blake Palculict20Hong Li21Guojun Zhang22Guojun Zhang23Faisal Zafar24Nuzhat Rana25Noriko Takashima26Hayato Matsunaga27Claudia Manzoni28Pasquale Striano29Pasquale Striano30Mark F. Lythgoe31Jun Aruga32Jun Aruga33Wei Lu34Henry Houlden35Department of Neuromuscular Disorders, University College London (UCL) Queen Square Institute of Neurology, London, United KingdomU.O.C. Genetica Medica, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, ItalySynapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United StatesDepartment of Biological Sciences, International Islamic University Islamabad, Islamabad, PakistanSynapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United StatesCentre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United KingdomDepartment of Neuromuscular Disorders, University College London (UCL) Queen Square Institute of Neurology, London, United KingdomDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, ItalyPediatric Neurology and Muscular Diseases Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, ItalyDepartment of Neuromuscular Disorders, University College London (UCL) Queen Square Institute of Neurology, London, United KingdomCentre for Omic Sciences, Islamia College Peshawar, Peshawar, PakistanSchool of Pharmacy, University of Reading, Reading, United Kingdom0Department of Mathematics and Statistics, University of Reading, Reading, United Kingdom1Department of Radiology, Great Ormond Street Hospital, London, United Kingdom2Developmental Neurosciences Department, University College London (UCL) Great Ormond Street Institute of Child Health, London, United KingdomDepartment of Neuromuscular Disorders, University College London (UCL) Queen Square Institute of Neurology, London, United KingdomDepartment of Neuromuscular Disorders, University College London (UCL) Queen Square Institute of Neurology, London, United KingdomDepartment of Neuromuscular Disorders, University College London (UCL) Queen Square Institute of Neurology, London, United Kingdom3Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States3Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States4GeneDx, Gaithersburg, MD, United States5Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States5Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States6Department of Pediatric Neurology, Children’s Healthcare of Atlanta, Atlanta, GA, United States7Department of Pediatrics, Multan Hospital, Multan, Pakistan7Department of Pediatrics, Multan Hospital, Multan, Pakistan8Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Saitama, Japan9Department of Medical Pharmacology, Nagasaki University Institute of Biomedical Sciences, Nagasaki, Japan0School of Pharmacy, University College London, London, United KingdomDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, ItalyPediatric Neurology and Muscular Diseases Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, ItalyCentre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom8Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Saitama, Japan9Department of Medical Pharmacology, Nagasaki University Institute of Biomedical Sciences, Nagasaki, JapanSynapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United StatesDepartment of Neuromuscular Disorders, University College London (UCL) Queen Square Institute of Neurology, London, United KingdomThis study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients’ SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3–/–) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.https://www.frontiersin.org/articles/10.3389/fnmol.2024.1222935/fullSLITRK3GABAergic synapse developmentepilepsyglobal developmental delayinhibitory synaptic transmissionNGS - next generation sequencing |
| spellingShingle | Stephanie Efthymiou Stephanie Efthymiou Wenyan Han Muhammad Ilyas Jun Li Yichao Yu Marcello Scala Marcello Scala Marcello Scala Nancy T. Malintan Muhammad Ilyas Nikoleta Vavouraki Nikoleta Vavouraki Kshitij Mankad Kshitij Mankad Reza Maroofian Clarissa Rocca Vincenzo Salpietro Shenela Lakhani Eric J. Mallack Timothy Blake Palculict Hong Li Guojun Zhang Guojun Zhang Faisal Zafar Nuzhat Rana Noriko Takashima Hayato Matsunaga Claudia Manzoni Pasquale Striano Pasquale Striano Mark F. Lythgoe Jun Aruga Jun Aruga Wei Lu Henry Houlden Human mutations in SLITRK3 implicated in GABAergic synapse development in mice Frontiers in Molecular Neuroscience SLITRK3 GABAergic synapse development epilepsy global developmental delay inhibitory synaptic transmission NGS - next generation sequencing |
| title | Human mutations in SLITRK3 implicated in GABAergic synapse development in mice |
| title_full | Human mutations in SLITRK3 implicated in GABAergic synapse development in mice |
| title_fullStr | Human mutations in SLITRK3 implicated in GABAergic synapse development in mice |
| title_full_unstemmed | Human mutations in SLITRK3 implicated in GABAergic synapse development in mice |
| title_short | Human mutations in SLITRK3 implicated in GABAergic synapse development in mice |
| title_sort | human mutations in slitrk3 implicated in gabaergic synapse development in mice |
| topic | SLITRK3 GABAergic synapse development epilepsy global developmental delay inhibitory synaptic transmission NGS - next generation sequencing |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1222935/full |
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