{
  "abstract": "Rare variants in GRIA3, the gene encoding the GluA3 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs), are associated with defects in early brain development. Disease-causing variants are generally categorised as either loss of function (LoF) or gain of function (GoF) that appear to be linked to different symptoms. Here, we reported a de novo variant (N651D) that has mixed LoF and GoF in a female patient with a devastating developmental and epileptic encephalopathy, parkinsonism and cortical malformation. N651D is located in the M3 segment, which forms the filter pore of AMPAR tetramers. Interestingly, functional assays revealed that glutamate induced no currents in GluA3_N651D homomeric receptors, likely indicating an LoF effect. However, when co-expressed with the GluA2 subunit, the GluA2/A3_N651D heteromeric receptors showed slower deactivation and desensitisation curves, along with elevated non-desensitising steady-state currents, features typically observed in GoF variants. We speculate that variants with mixed LoF and GoF effects may lead to a more devastating phenotype compared with variants with GoF effects only.",
  "authors": [
    {
      "affiliations": [
        "Sant Joan de Deu Hospital, Barcelona, 08-Barcelona, Spain"
      ],
      "name": "Carmen Fons"
    },
    {
      "affiliations": [
        "Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School, Nanjing University, Nanjing, Jiangsu, China"
      ],
      "name": "Yu-Han Ge"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Danish Epilepsy Center, Dianalund, Denmark"
      ],
      "name": "Laura Kristine Rasmussen"
    },
    {
      "affiliations": [
        "Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School, Nanjing University, Nanjing, Jiangsu, China"
      ],
      "name": "Yun Stone Shi"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Danish Epilepsy Center, Dianalund, Denmark",
        "Department of Regional Health Research, University of Southern Denmark, Odense, Denmark"
      ],
      "name": "Allan Bayat"
    }
  ],
  "title": "Mixed functional consequences of the N651D GRIA3 variant: a case of early-onset developmental and epileptic encephalopathy with parkinsonism",
  "uid": "a75d4039-eed9-599c-aae5-8e322dcdf90b"
}