TY - JOUR
T1 - Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans
AU - Wu, Ye
AU - Arai, Amy C.
AU - Rumbaugh, Gavin
AU - Srivastava, Anand K.
AU - Turner, Gillian
AU - Hayashi, Takashi
AU - Suzuki, Erika
AU - Jiang, Yuwu
AU - Zhang, Lilei
AU - Rodriguez, Jayson
AU - Boyle, Jackie
AU - Tarpey, Patrick
AU - Raymond, F. Lucy
AU - Nevelsteen, Joke
AU - Froyen, Guy
AU - Stratton, Mike
AU - Futreal, Andy
AU - Gecz, Jozef
AU - Stevenson, Roger
AU - Schwartz, Charles E.
AU - Valle, David
AU - Huganir, Richard L.
AU - Wang, Tao
PY - 2007/11/13
Y1 - 2007/11/13
N2 - Ionotropic α-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.
AB - Ionotropic α-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.
KW - Glutamate receptor
KW - X-linked mental retardation
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U2 - 10.1073/pnas.0708699104
DO - 10.1073/pnas.0708699104
M3 - Article
C2 - 17989220
AN - SCOPUS:36749009127
SN - 0027-8424
VL - 104
SP - 18163
EP - 18168
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
ER -