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学科主题: 临床医学
题名:
Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans
作者: Wu, Ye; Arai, Amy C.; Rumbaugh, Gavin; Srivastava, Anand K.; Turner, Gillian; Hayashi, Takashi; Suzuki, Erika; Jiang, Yuwu; Zhang, Lile; Rodriguez, Jayson; Boyle, Jackie; Tarpey, Patrick; Raymond, F. Lucy; Nevelsteen, Joke; Froyen, Guy; Stratton, Mike; Futreal, Andy; Gecz, Jozef; Stevenson, Roger; Schwartz, Charles E.; Valle, David; Huganir, Richard L.; Wang, Tao
关键词: glutamate receptor ; X-linked mental retardation
刊名: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
发表日期: 2007-11-13
DOI: 10.1073/pnas.0708699104
卷: 104, 期:46, 页:18163-18168
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
关键词[WOS]: LINKED MENTAL-RETARDATION ; LONG-TERM POTENTIATION ; GLUTAMATE RECEPTORS ; SYNAPTIC PLASTICITY ; MOLECULAR-BIOLOGY ; ION CHANNELS ; MEMORY ; HIPPOCAMPUS ; PREVALENCE ; MODULATOR
英文摘要:

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 GRlA3 (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.

语种: 英语
WOS记录号: WOS:000251077000049
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/65665
Appears in Collections:北京大学第一临床医学院_儿科_期刊论文

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作者单位: 1.Univ Adelaide, Dept Mol Biosci, Adelaide, SA 5005, Australia
2.Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA
3.Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA
4.Greenwood Genet Ctr, Greenwood, SC 29646 USA
5.Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England
6.Univ Adelaide, Dept Pediat, Adelaide, SA 5005, Australia
7.Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
8.Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA
9.So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA
10.Univ Newcastle, Hunter Genet & Genet Learning Disabil GOLD Serv, Newcastle, NSW 2308, Australia
11.Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 2XY, England
12.Katholieke Univ Leuven, Vlaams Inst Biotechnol, Dept Human Genet, Human Genome Lab, B-3000 Louvain, Belgium
13.Univ Adelaide, Womens & Childrens Hosp, Dept Med Genet, Adelaide, SA 5005, Australia
14.Beijing Univ, Hosp 1, Dept Pediat, Beijing 100034, Peoples R China

Recommended Citation:
Wu, Ye,Arai, Amy C.,Rumbaugh, Gavin,et al. Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2007,104(46):18163-18168.
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