Journal
BRAIN
Volume 145, Issue 3, Pages 909-924Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awab369
Keywords
biallelic; SLC38A3; glutamate transporter; glutamate/GABA-glutamine cycle
Categories
Funding
- U.S. National Human Genome Research Institute (NHGRI)
- National Heart Lung and Blood Institute (NHBLI) [UM1 HG006542]
- NHGRIgrant [U54HG003273]
- U.S. National Institute of Neurological Disorders and Stroke (NINDS) [R35NS105078]
- Muscular Dystrophy Association (MDA) [512848]
- Qatar National Research Fund (QNRF) [NPRP11S-0110180250]
- Wellcome Trust [WT093205 MA, WT104033AIA]
- Queen Square Genomics group at University College London
- National Institute for Health Research University College London Hospitals Biomedical Research Centre [MR/S01165X/1, MR/S005021/1, G0601943]
- Rosetree Trust, Ataxia UK
- MSA Trust
- Brain Research UK
- Sparks GOSH Charity
- Muscular Dystrophy UK (MDUK)
- Muscular Dystrophy Association (MDA USA)
- Medical Genetics Research Fellowship Program through the United States National Institute of Health [T32 GM007526-42]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme
- Wellcome Trust Core Award [203141/Z/16/Z]
- Uehara Memorial Foundation
- International Rett Syndrome Foundation (IRSF) [3701-1]
- NHGRI [K08 HG008986]
- Isabelle Rapin Scholar Recipient for clinical research in autoimmune encephalitis
Ask authors/readers for more resources
SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy, and the likely pathophysiology of the disease is perturbations in glutamine homeostasis.
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.
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