Human Gene Module / Chromosome 12 / GRIP1

GRIP1glutamate receptor interacting protein 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 12
Rare Variants / Common Variants
10 / 1
Aliases
GRIP1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
12q14.3
Associated Disorders
-
Relevance to Autism

Rare variants and genetic association have been found with the GRIP1 gene and autism in AGRE and SCAP cohorts (Mejias et al., 2011). In particular, that study showed convincing higher incidence of missense variants in 480 cases compared to 480 controls. Although segregation within pedigrees was not perfect, the variants were shown to be functional due to altered binding to glutamate receptor 2/3.

Molecular Function

The encoded scaffold protein mediates trafficking and membrane organization of various transmembrane proteins.

Reports related to GRIP1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Setou M , et al. (2002) No -
2 Recent Recommendation A role for SNAP25 in internalization of kainate receptors and synaptic plasticity. Selak S , et al. (2009) No -
3 Recent Recommendation Expression profiles of schizophrenia susceptibility genes during human prefrontal cortical development. Choi KH , et al. (2009) No -
4 Recent Recommendation Differential roles of GRIP1a and GRIP1b in AMPA receptor trafficking. Hanley LJ and Henley JM (2010) No -
5 Recent Recommendation GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions. Mao L , et al. (2010) No -
6 Primary Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism. Mejias R , et al. (2011) Yes -
7 Support Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Kenny EM , et al. (2013) Yes -
8 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
9 Recent Recommendation Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade. Gainey MA , et al. (2015) No -
10 Recent Recommendation GRIP1 is required for homeostatic regulation of AMPAR trafficking. Tan HL , et al. (2015) No -
11 Highly Cited GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Hong H , et al. (1996) No -
12 Highly Cited GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Hong H , et al. (1997) No -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1649C>T p.Thr550Met missense_variant Unknown - Simplex 21383172 Mejias R , et al. (2011)
c.1756A>C p.Ile586Leu missense_variant Familial Paternal Multiplex 21383172 Mejias R , et al. (2011)
c.1873G>A p.Ala625Thr missense_variant Familial Paternal Multiplex 21383172 Mejias R , et al. (2011)
c.2381T>G p.Met794Arg missense_variant Familial Both parents Multiplex 21383172 Mejias R , et al. (2011)
c.160G>A p.Val54Ile missense_variant - - - 21383172 Mejias R , et al. (2011)
c.2461C>G p.Gln821Glu missense_variant - - - 21383172 Mejias R , et al. (2011)
c.2606G>A p.Arg869Gln missense_variant - - - 21383172 Mejias R , et al. (2011)
c.2856+2T>A - splice_site_variant Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.445C>T p.Arg149Ter stop_gained Unknown - Unknown 24126926 Kenny EM , et al. (2013)
c.1446C>T p.(=) synonymous_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1682+13G>T;c.1841+13G>T;c.1838+13G>T;c.1760+13G>T;c.1685+13G>T - intron_variant - - - 21383172 Mejias R , et al. (2011)
SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

7/1/2015
2
icon
2

Score remained at 2

Description

Rare variants and genetic association have been found with the GRIP1 gene and autism in AGRE and SCAP cohorts (Mejias et al., 2011). In particular, that study showed convincing higher incidence of missense variants in 480 cases compared to 480 controls. Although segregation within pedigrees was not perfect, the variants were shown to be functional due to altered binding to glutamate receptor 2/3.

1/1/2015
2
icon
2

Score remained at 2

Description

Rare variants and genetic association have been found with the GRIP1 gene and autism in AGRE and SCAP cohorts (Mejias et al., 2011). In particular, that study showed convincing higher incidence of missense variants in 480 cases compared to 480 controls. Although segregation within pedigrees was not perfect, the variants were shown to be functional due to altered binding to glutamate receptor 2/3.

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Rare variants and genetic association have been found with the GRIP1 gene and autism in AGRE and SCAP cohorts (Mejias et al., 2011). In particular, that study showed convincing higher incidence of missense variants in 480 cases compared to 480 controls. Although segregation within pedigrees was not perfect, the variants were shown to be functional due to altered binding to glutamate receptor 2/3.

4/1/2014
No data
icon
2

Increased from No data to 2

Description

Rare variants and genetic association have been found with the GRIP1 gene and autism in AGRE and SCAP cohorts (Mejias et al., 2011). In particular, that study showed convincing higher incidence of missense variants in 480 cases compared to 480 controls. Although segregation within pedigrees was not perfect, the variants were shown to be functional due to altered binding to glutamate receptor 2/3.

Krishnan Probability Score

Score 0.49519849294128

Ranking 3128/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.91689496809662

Ranking 3067/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.9454938095147

Ranking 16492/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 28

Ranking 75/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.20220772395444

Ranking 4230/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with GRIP1(1 CNVs)
12q14.3 7 Deletion-Duplication 12  /  15
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CREBBP (CBP) CREB binding protein Human Protein Binding 1387 Q92793
CSPG4 chondroitin sulfate proteoglycan 4 Rat Protein Binding 81651 Q00657
FLI-I Protein flightless-1 homolog Human Protein Binding 9606 Q13045
GluA2 Glutamate receptor 2 Mouse Protein Binding 14800 P23819
GluR3 glutamate receptor, ionotropic, AMPA3 (alpha 3) Mouse Protein Binding 53623 Q9Z2W9
GluR4a glutamate receptor, ionotropic, AMPA4 (alpha 4) Mouse Protein Binding 14802 Q9Z2W8
GluR6 glutamate receptor, ionotropic, kainate 2 (beta 2) Mouse Protein Binding 14806 P39087
GluR7a glutamate receptor, ionotropic, kainate 3 Mouse Protein Binding 14807 B1AS29
GluR7b glutamate receptor, ionotropic, kainate 3 Mouse Protein Binding 14807 B1AS29
GRIK1 glutamate receptor, ionotropic, kainate 1 Rat Protein Binding 29559 P22756
KIF5 kinesin family member 5A Mouse Protein Binding 16572 P33175
Merm1 Ribosome biogenesis methyltransferase WBSCR22 Human Protein Binding 114049 O43709
NR1I2 nuclear receptor subfamily 1, group I, member 2 Human Protein Binding 18171 O75469
NUMBL numb homolog (Drosophila)-like Rat Protein Binding 292732 A1L1I3
PLAGL1 pleiomorphic adenoma gene-like 1 Mouse Protein Binding 22634 Q9JLQ4
PRLHR prolactin releasing hormone Human Protein Binding 51052 P81277
Sec8 exocyst complex component 4 Mouse Protein Binding 60412 Q96A65
TR-B thyroid hormone receptor, beta Human Protein Binding 7068 P10828
VDR vitamin D (1,25- dihydroxyvitamin D3) receptor Human Protein Binding 7421 P11473
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