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Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism.

Glutamate receptor interacting protein 1 (GRIP1) is a neuronal scaffolding protein that interacts directly with the C termini of glutamate receptors 2/3 (GluA2/3) via its PDZ domains 4 to 6 (PDZ4-6). We found an association (P<0.05) of a SNP within the PDZ4-6 genomic region with autism by genotyping autistic patients (n=480) and matched controls (n=480). Parallel sequencing identified five rare missense variants within or near PDZ4-6 only in the autism cohort, resulting in a higher cumulative mutation load (P=0.032). Two variants correlated with a more severe deficit in reciprocal social interaction in affected sibling pairs from proband families. These variants were associated with altered interactions with GluA2/3 and faster recycling and increased surface distribution of GluA2 in neurons, suggesting gain-of-function because GRIP1/2 deficiency showed opposite phenotypes. Grip1/2 knockout mice exhibited increased sociability and impaired prepulse inhibition. These results support a role for GRIP in social behavior and implicate GRIP1 variants in modulating autistic phenotype.

Pubmed ID: 21383172


  • Mejias R
  • Adamczyk A
  • Anggono V
  • Niranjan T
  • Thomas GM
  • Sharma K
  • Skinner C
  • Schwartz CE
  • Stevenson RE
  • Fallin MD
  • Kaufmann W
  • Pletnikov M
  • Valle D
  • Huganir RL
  • Wang T


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 22, 2011

Associated Grants

  • Agency: NIMH NIH HHS, Id: 1U24MH081810
  • Agency: Autism Speaks, Id: AS2487
  • Agency: NICHD NIH HHS, Id: R01HD052680
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Autistic Disorder
  • Carrier Proteins
  • Cells, Cultured
  • Child
  • Cohort Studies
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation, Missense
  • Nerve Tissue Proteins
  • Neurons
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary
  • Rats
  • Receptors, Glutamate