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

Abstract

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.

• Authors: Rebeca Mejias, Abby Adamczyk, Victor Anggono, Tejasvi Niranjan, Gareth M Thomas, Kamal Sharma, Cindy Skinner, Charles E Schwartz, Roger E Stevenson, M Daniele Fallin, Walter Kaufmann, Mikhail Pletnikov, David Valle, Richard L Huganir, Tao Wang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 12 Pg. 4920-5 (Mar 22 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21383172 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• GRIP1 protein, human
• Grip1 protein, mouse
• Grip1 protein, rat
• Grip2 protein, mouse
• Intracellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• Receptors, Glutamate

Topics

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