Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy
Year: 2021
Type: article
Abstract: The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.
Source: Brain
Authors: Dana Marafi, Jawid M Fatih, Rauan Kaiyrzhanov, Matteo P Ferla, Charul Gijavanekar, Aljazi Al-Maraghi, Ning Liu, Emily Sites, Hessa S Alsaif, Mohammad Al-Owain, Mohamed Zakkariah, Ehab El-Anany, Ulviyya Guliyeva, Sughra Guliyeva, Colette Gaba, Ateeq Haseeb, Amal M Alhashem, Enam Danish, Vasiliki Karageorgou, Christian Beetz, Alaa A Subhi, Sureni V Mullegama, Erin Torti, Monisha Sebastin, Margo Sheck Breilyn, Susan Duberstein, Mohamed S Abdel-Hamid, Tadahiro Mitani, Haowei Du, Jill A Rosenfeld, Shalini N Jhangiani, Zeynep Coban Akdemir, Richard A Gibbs, Jenny C Taylor, Khalid A Fakhro, Jill V Hunter, Davut Pehlivan, Maha S Zaki, Joseph G Gleeson, Reza Maroofian, Henry Houlden, Jennifer E Posey, V Reid Sutton, Fowzan S Alkuraya, Sarah H Elsea, James R Lupski
Institutions: Baylor College of Medicine, Kuwait University, UCL Queen Square Institute of Neurology, University College London, Centre for Human Genetics, University of Oxford, NIHR Oxford Biomedical Research Centre, Baylor Genetics, Sidra Medical and Research Center, Nationwide Children's Hospital, King Faisal Specialist Hospital & Research Centre, Alfaisal University, Adan Hospital, Bon Secours Mercy Health, Mercy Children's Hospital, Riyadh Armed Forces Hospital, King Fahd Armed Forces Hospital, King Fahad Hospital Jeddah, Centogene (Germany), Albert Einstein College of Medicine, Montefiore Medical Center, Children's Hospital at Montefiore, Icahn School of Medicine at Mount Sinai, National Research Centre, The University of Texas Health Science Center at Houston, Hamad bin Khalifa University, Weill Cornell Medical College in Qatar, Texas Children's Hospital, Howard Hughes Medical Institute, University of California San Diego, Rady Children's Institute for Genomic Medicine
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: International Rett Syndrome Foundation, Muscular Dystrophy Association, Uehara Memorial Foundation, Wellcome Trust, Qatar National Research Fund, Medical Research Council, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Human Genetics and Disease Biology: Core Renewal for the Wellcome Trust Centre for Human Genetics, Understanding non-coding genomic variation in neurological disorders, G1704489350, Individual genomic analyses to discover the molecular basis and mechanisms contributing to adult-onset disease, Synaptopathies: genetics, biophysics and circuit mechanisms of paroxysmal neurological disorders., The Human Genome Sequencing Center, Baylor Johns Hopkins Center for Mendelian Genetics, G5680352538, Development of an Institute of Neurology Next Generation Sequencing Facility Equipment Grant., G6524192475, G6608967203, G736941631, Leveraging the power of genomics and transcriptomics to revolutionise the diagnosis and understanding of neurological disorders, Medical Genetics Research Fellowship Program, STRUCTURAL VARIATION IN NEUROLOGICAL DISEASE
OpenAlex ID: W3203673145