Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans.
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.
Wu
Ye
Y
Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Arai
Amy C
AC
Rumbaugh
Gavin
G
Srivastava
Anand K
AK
Turner
Gillian
G
Hayashi
Takashi
T
Suzuki
Erika
E
Jiang
Yuwu
Y
Zhang
Lilei
L
Rodriguez
Jayson
J
Boyle
Jackie
J
Tarpey
Patrick
P
Raymond
F Lucy
FL
Nevelsteen
Joke
J
Froyen
Guy
G
Stratton
Mike
M
Futreal
Andy
A
Gecz
Jozef
J
Stevenson
Roger
R
Schwartz
Charles E
CE
Valle
David
D
Huganir
Richard L
RL
Wang
Tao
T
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*
D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3