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

McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, The Howard Hughes Medical Institute, Predoctoral Training Program in Human Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2011; 108(12):4920-5. DOI: 10.1073/pnas.1102233108
Source: PubMed


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.

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    • "were located in glutamate receptor interacting protein 1 (GRIP1) and ankyrin repeat and sterile alpha motif domain containing 1B (ANKS1B). Many studies have found GRIP1 plays an important role in receptor trafficking, synaptic organization, transmission in glutamatergic and GABAergic synapses and modulating autistic phenotype [22]–[24]. But unfortunately, little is known about the function of GRIP1 in livestock. "
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    • "There is evidence that correct protein trafficking is important for cognition. For example, deletion of the glutamate receptor interacting protein GRIP in mice results in impairments in PPI, novel object recognition, and sociability (Mejias et al. 2011). In addition , recent studies strongly suggest that insulin-like growth factor 2 (IGF2) enhances memory consolidation (Alberini and Chen 2012). "
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    • "Those findings led Bakshi et al. to propose suppressing the excessive GRIP1 phosphorylation as a therapeutic to treat the consequences of prenatal cocaine exposure. In addition, a recent study has linked changes in the function of GRIP1 with autism in humans (Mejias et al., 2011). Sequencing of GRIP1 in individuals with autism uncovered five rare missense variants in the genomic sequence near the encoding of PDZ4-6. "
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