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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Available from: Victor Anggono, Oct 04, 2015
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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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    ABSTRACT: Sheep are among the major economically important livestock species worldwide because the animals produce milk, wool, skin, and meat. In the present study, the Illumina OvineSNP50 BeadChip was used to investigate genetic diversity and genome selection among Suffolk, Rambouillet, Columbia, Polypay, and Targhee sheep breeds from the United States. After quality-control filtering of SNPs (single nucleotide polymorphisms), we used 48,026 SNPs, including 46,850 SNPs on autosomes that were in Hardy-Weinberg equilibrium and 1,176 SNPs on chromosome × for analysis. Phylogenetic analysis based on all 46,850 SNPs clearly separated Suffolk from Rambouillet, Columbia, Polypay, and Targhee, which was not surprising as Rambouillet contributed to the synthesis of the later three breeds. Based on pair-wise estimates of F ST, significant genetic differentiation appeared between Suffolk and Rambouillet (F ST = 0.1621), while Rambouillet and Targhee had the closest relationship (F ST = 0.0681). A scan of the genome revealed 45 and 41 differentially selected regions (DSRs) between Suffolk and Rambouillet and among Rambouillet-related breed populations, respectively. Our data indicated that regions 13 and 24 between Suffolk and Rambouillet might be good candidates for evaluating breed differences. Furthermore, ovine genome v3.1 assembly was used as reference to link functionally known homologous genes to economically important traits covered by these differentially selected regions. In brief, our present study provides a comprehensive genome-wide view on within- and between-breed genetic differentiation, biodiversity, and evolution among Suffolk, Rambouillet, Columbia, Polypay, and Targhee sheep breeds. These results may provide new guidance for the synthesis of new breeds with different breeding objectives.
    PLoS ONE 06/2013; 8(6):e65942. DOI:10.1371/journal.pone.0065942 · 3.23 Impact Factor
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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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    ABSTRACT: AMPA-receptor trafficking plays a central role in excitatory plasticity, especially during development. Changes in the number of AMPA receptors and time spent at the synaptic surface are important factors of plasticity that directly affect long-term potentiation (LTP), long-term depression (LTD), synaptic scaling, and the excitatory-inhibitory (E/I) balance in the developing cortex. Experience-dependent changes in synaptic strength in visual cortex (V1) use a molecularly distinct AMPA trafficking pathway that includes the GluA2 subunit. We studied developmental changes in AMPA receptor trafficking proteins by quantifying expression of GluA2, pGluA2 (GluA2serine880), GRIP1, and PICK1 in rat visual and frontal cortex. We used Western Blot analysis of synaptoneurosome preparations of rat visual and frontal cortex from animals ranging in age from P0 to P105. GluA2 and pGluA2 followed different developmental trajectories in visual and frontal cortex, with a brief period of over expression in frontal cortex. The over expression of GluA2 and pGluA2 in immature frontal cortex raises the possibility that there may be a period of GluA2-dependent vulnerability in frontal cortex that is not found in V1. In contrast, GRIP1 and PICK1 had the same developmental trajectories and were expressed very early in development of both cortical areas. This suggests that the AMPA-interacting proteins are available to begin trafficking receptors as soon as GluA2-containing receptors are expressed. Finally, we used all four proteins to analyze the surface-to-internalization balance and found that this balance was roughly equal across both cortical regions, and throughout development. Our finding of an exquisite surface-to-internalization balance highlights that these AMPA receptor trafficking proteins function as a tightly controlled system in the developing cortex.
    Frontiers in Molecular Neuroscience 05/2012; 5:65. DOI:10.3389/fnmol.2012.00065 · 4.08 Impact Factor
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    • "GRIP1 is a member of the glutamate receptor interacting proteins and has been reported to show altered expression in schizophrenia brain [36,37]. A study of genotyped autistic patients and matched controls showed an association of a SNP within a genomic region of GRIP1 with autism [38]. Linkage to the region containing, SLC1A1, a glutamate transporter, has been reported for obsessive compulsive disorder [39,40], and a SNP near SLC1A1 was reported to show association with autism spectrum disorder [41]. "
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    BMC Medical Genetics 11/2011; 12(1):154. DOI:10.1186/1471-2350-12-154 · 2.08 Impact Factor
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