title: Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans.
abstract: Ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (iGluRs) mediate the majority of excitatory synaptic transmission in the CNS and are essential for the induction and maintenance of long-term potentiation and long-term depression, two cellular models of learning and memory. We identified a genomic deletion (0.4 Mb) involving the entire GRIA3 (encoding iGluR3) by using an X-array comparative genomic hybridization (CGH) and four missense variants (G833R, M706T, R631S, and R450Q) in functional domains of iGluR3 by sequencing 400 males with X-linked mental retardation (XLMR). Three variants were found in males with moderate MR and were absent in 500 control males. Expression studies in HEK293 cells showed that G833R resulted in a 78% reduction of iGluR3 due to protein misfolding. Whole-cell recording studies of iGluR3 homomers in HEK293 cells revealed that neither iGluR3-M706T (S2 domain) nor iGluR3-R631S (near channel core) had substantial channel function, whereas R450Q (S1 domain) was associated with accelerated receptor desensitization. When forming heteromeric receptors with iGluR2 in HEK293 cells, all four iGluR3 variants had altered desensitization kinetics. Our study provides the genetic and functional evidence that mutant iGluR3 with altered kinetic properties is associated with moderate cognitive impairment in humans.
authors.affiliation: Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wu
authors.forename: Amy C
authors.initials: AC
authors.lastname: Arai
authors.forename: Gavin
authors.initials: G
authors.lastname: Rumbaugh
authors.forename: Anand K
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Erika
authors.initials: E
authors.lastname: Suzuki
authors.forename: Yuwu
authors.initials: Y
authors.lastname: Jiang
authors.forename: Lilei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jayson
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Jackie
authors.initials: J
authors.lastname: Boyle
authors.forename: Patrick
authors.initials: P
authors.lastname: Tarpey
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.forename: Joke
authors.initials: J
authors.lastname: Nevelsteen
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
authors.forename: Mike
authors.initials: M
authors.lastname: Stratton
authors.forename: Andy
authors.initials: A
authors.lastname: Futreal
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Roger
authors.initials: R
authors.lastname: Stevenson
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: David
authors.initials: D
authors.lastname: Valle
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D018091:Receptors, AMPA / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
chemical_list: D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3