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@ARTICLE{Kovermann:1041341,
      author       = {Kovermann, Peter and Bayat, Allan and Fenger, Christina D.
                      and Leeuwen, Lisette and Borovikov, Artem and Sharkov, Artem
                      and Levrat, Virginie and Lesca, Gaetan and Perrin, Laurence
                      and Levy, Jonathan and Fahlke, Christoph and Møller, Rikke
                      S. and Jensen, Anders A.},
      title        = {{T}he severity of {SLC}1{A}2-associated neurodevelopmental
                      disorders correlates with transporter dysfunction},
      journal      = {EBioMedicine},
      volume       = {114},
      issn         = {2352-3964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2025-02231},
      pages        = {105648 -},
      year         = {2025},
      note         = {We thank the patients and families who participated in the
                      collection of clinical data for this project and for
                      enrolling in our research studies. Drs. M. Hediger
                      (Universität Bern, Switzerland) and S.G. Amara (National
                      Institutes of Health, Bethesda, MD) are thanked for their
                      generous gifts of EAAT2 cDNAs. AAJ was supported by the
                      Lundbeck Foundation, and ChF was supported by the German
                      Ministry of Education and Research (BMBF 01GM2210D, E-RARE
                      network, Treat-ION).},
      abstract     = {L-Glutamate (L-Glu) is the major excitatory
                      neurotransmitter in the human brain, where it is involved in
                      or contributes to essentially all central functions.
                      Glutamatergic hyper- or hypofunction have been linked to a
                      range of neurological, cognitive, and psychiatric disorders,
                      and thus glutamatergic receptors, transporters and enzymes
                      constitute promising therapeutic targets.1, 2, 3Following
                      its release from presynaptic terminals, L-Glu is quickly
                      taken up into glia and neurons by five excitatory amino acid
                      transporters (EAAT1-5) from solute carrier 1 (SLC1) family
                      of Na+-dependent transporters.4, 5, 6 The EAAT functions as
                      a homotrimeric assembly, with each monomer comprising
                      intracellular amino- and carboxy-termini, eight
                      transmembrane domains (TM1-8) and two hairpin structures
                      (HP1-2) with interconnecting extra- and intracellular
                      loops.5,7,8 The transport domain (TM3,6–8, HP1-2) in the
                      monomer mediates stoichiometrically coupled L-Glu transport
                      via an elevator mechanism driven by co-transport of three
                      Na+ and one H+ and counter-transport of one K+, while the
                      trimerization domain (TM1-2,4–5) is anchored to the plasma
                      membrane making inter-monomeric contacts.5,7, 8, 9, 10 EAATs
                      also act as anion channels that open and close during
                      transitions along the L-Glu transport cycle via brief gap
                      openings between the transport and trimerization domains.11,
                      12, 13, 14, 15Variants in SLC1A1-3 and SLC1A6-7 encoding for
                      the five EAATs have been linked with various neurological
                      and neuropsychiatric disorders.16,17 For example, we and
                      others have found missense SLC1A3 variants associated with
                      episodic ataxia 6 to change EAAT1 anion channel
                      conduction.13,18, 19, 20, 21 EAAT2, the predominant glial
                      and presynaptic EAAT subtype, is abundantly expressed
                      throughout the brain, where it mediates $∼90\%$ of total
                      central L-Glu uptake,4,22,23 which makes SLC1A2 variants of
                      potential importance for a range of central nervous system
                      (CNS) disorders.24, 25, 26 Recently, three missense SLC1A2
                      variants associated with developmental and epileptic
                      encephalopathies (DEEs)27, 28, 29, 30 were reported to
                      significantly alter EAAT2 anion channel function.24 However,
                      the SLC1A2-related phenotype remains ill-defined, and
                      genotype-phenotype correlations have not been reported.With
                      the present study we aim to provide the first
                      genotype-phenotype correlation analysis for SLC1A2, to
                      elucidate the molecular phenotypic basis for
                      SLC1A2-associated neurodevelopmental disorders, and to
                      provide the basis for future predictions of disease
                      progression and severity of these. We present a cohort of 18
                      individuals with 13 presumed pathogenic SLC1A2 variants
                      presenting with neurodevelopmental disorders and DEEs. We
                      delineate the effects induced by nine novel missense
                      variants on EAAT2 expression and function via heterologous
                      expression of wild-type (WT) and mutant transporters in
                      mammalian cell lines, and we deep-phenotype the
                      neurodevelopmental disorders and epileptology associated
                      with SLC1A2 variants.},
      cin          = {IBI-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-1-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524) / Treat-ION - Neue Therapien für neurologische
                      Ionenkanal- und Transporterstörungen - Teilprojekt 6
                      Zelluläre Pathophysiologie (01GM1907C)},
      pid          = {G:(DE-HGF)POF4-5241 / G:(BMBF)01GM1907C},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1016/j.ebiom.2025.105648},
      url          = {https://juser.fz-juelich.de/record/1041341},
}