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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.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism.
ASD
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Unknown diagnosis
Support
Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.
ASD, SCZ
Support
Integrating de novo and inherited variants in 42
ASD
Support
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
ASD
Highly Cited
GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors.
Highly Cited
GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors.
Highly Cited
Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites.
Recent Recommendation
A role for SNAP25 in internalization of kainate receptors and synaptic plasticity.
Recent Recommendation
GRIP1 is required for homeostatic regulation of AMPAR trafficking.
Recent Recommendation
Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade.
Recent Recommendation
GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions.
Recent Recommendation
Differential roles of GRIP1a and GRIP1b in AMPA receptor trafficking.
Recent Recommendation
Expression profiles of schizophrenia susceptibility genes during human prefrontal cortical development.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN112R001 
 missense_variant 
 c.1649C>T 
 p.Thr550Met 
 Unknown 
  
 Simplex 
 GEN112R002 
 missense_variant 
 c.1756A>C 
 p.Ile586Leu 
 Familial 
 Paternal 
 Multiplex 
 GEN112R003 
 missense_variant 
 c.1873G>A 
 p.Ala625Thr 
 Familial 
 Paternal 
 Multiplex 
 GEN112R004a 
 missense_variant 
 c.2381T>G 
 p.Leu794Trp 
 Familial 
 Both parents 
 Multiplex 
 GEN112R005 
 missense_variant 
 c.160G>A 
 p.Val54Ile 
  
  
  
 GEN112R006 
 missense_variant 
 c.2461C>G 
 p.Gln821Glu 
  
  
  
 GEN112R007 
 missense_variant 
 c.2606G>A 
 p.Arg869Lys 
  
  
  
 GEN112R008 
 splice_site_variant 
 c.2811+2T>A 
  
 Unknown 
  
 Unknown 
 GEN112R009 
 stop_gained 
 c.445C>T 
 p.Arg149Ter 
 Unknown 
  
 Unknown 
 GEN112R010 
 synonymous_variant 
 c.1446C>T 
 p.Asp482= 
 De novo 
  
 Unknown 
 GEN112R011 
 stop_gained 
 c.43C>T 
 p.Arg15Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN112R012 
 synonymous_variant 
 c.2388C>T 
 p.Ser796%3D 
 De novo 
  
  
 GEN112R013 
 splice_region_variant 
 c.2030A>G 
 p.Lys677Arg 
 De novo 
  
  

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN112C001 
 intron_variant 
 rs7397862 
 c.1682+13G>T;c.1841+13G>T;c.1838+13G>T;c.1760+13G>T;c.1685+13G>T 
  
 AGRE, SCAP 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
12
Duplication
 1
 
12
Deletion
 1
 
12
Deletion
 1
 
12
Deletion
 1
 
12
Deletion-Duplication
 9
 
12
Deletion
 2
 

Model Summary

Inactivation of Grip1 causes Fraser syndrome-like defects in mice. Grip1/Grip2 double knockout mice show increased sociability in a modified three-chamber social behavioral test and in a dyadic male-male social interaction test. Immunoblot studies identified an increase in phosphorylation at GluA2-Serine 880 (GluA2-pS880) in frontal cortex and reduced GABA3 expression in striatum.

References

Type
Title
Author, Year
Primary
A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1.
Mice lacking GRIP1/2 show increased social interactions and enhanced phosphorylation at GluA2-S880.

M_GRIP1_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Homologous recombination mediated targeted deletion of PDZ domain 1 of Grip1 gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57B1/6
Genetic Background: 129 X C56B1/6
ES Cell Line: R1
Mutant ES Cell Line: Not Reported
Model Source: Not Reported

M_GRIP1_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Homologous recombination mediated targeted deletion of PDZ domain 1 of Grip1 gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: C57B1/6
Genetic Background: C56B1/6
ES Cell Line: R1
Mutant ES Cell Line: Not Reported
Model Source: Not Reported

M_GRIP1_3_CKO_GRIP2_DM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of the first exon of the PDZ domain of the Grip1 gene using Nestin-Cre, in neuronal, glial and other cell types in the central and peripheral nervous system. The double mutant mice are generated by intercrossing the Grip1 conditonal knockout line with a Grip2 conventional knockout line.
Allele Type: Conditional loss-of-function
Strain of Origin: C57B1/6
Genetic Background: C57B1/6
ES Cell Line:
Mutant ES Cell Line: Not Reported
Model Source: Not Reported

M_GRIP1_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Mortality/lethality1
Increased
Description: Increased lethality resulting from hemorrhagic blisters
Exp Paradigm: General observations
 General observations
 E13.5
Developmental trajectory1
Abnormal
Description: Abnormal epithelial development demonstrated by detachment of oral and nasal cavities and blisters underneath head, limb, back skin
Exp Paradigm: General observations
 General observations
 E11
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_GRIP1_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Developmental trajectory1
Abnormal
Description: Abnormal limb development highlighted from highlighted syndactly of all digits to polydactyly
Exp Paradigm: General observations
 General observations
 Unreported
Developmental trajectory1
Abnormal
Description: Abnormal developmental trajectory indicated by unstructured mesenchymal rudiments remaining devoid of metanephric tubules with large number of apoptotic cells
Exp Paradigm: Tunel & dapi staining of embryonic tissue
 Tunel assay
 E13.5
Developmental trajectory1
Abnormal
Description: Abnormal steps of early metanephric development: no assembly of mesenchymal condensation around ureteric bud, induction of wilms' tumor antigen-1 (wt1)
Exp Paradigm: Immunofluoroscence staining of embryonic sections
 Immunohistochemistry
 E11.5
Protein expression level evidence1
Decreased
Description: Decreased expression of ecm proteins: collagen v, vi, substrates for ng2 and fras1 in basement membrane region
Exp Paradigm: Ecm protein expression
 Immunohistochemistry
 Unreported
Protein expression level evidence1
Abnormal
Description: Abnormally decreased expression of fras1 and retention in keratinocyte layer of epidermis
Exp Paradigm: Fras1 protein expression
 Immunohistochemistry
 Unreported
Protein expression level evidence1
Decreased
Description: Decreased expression/accumulation of ng2 in the epidermal-dermnal junction of embryonic skin
Exp Paradigm: Ng2 expression
 Immunohistochemistry
 Unreported
Developmental trajectory1
 No change
 General observations
 E16.5
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_GRIP1_3_CKO_GRIP2_DM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Social interaction1
Increased
Description: Grip1/2 double knockout mice exhibit increased social interactions relative wildtype controls
Exp Paradigm: Reciprocal social interaction test: male only
 Reciprocal social interaction test
 4 months
Social approach1
Increased
Description: Grip1/2 double knockout mice exhibit increased sociablity and preference for social novelty relative to wildtype controls
Exp Paradigm: Three-chamber social approach test
 Three-chamber social approach test
 3 months
Protein phosphorylation1
Increased
Description: Increased level of phosphorylated glua2 at serine 880 in front cortex and cerebellum of grip1/2 double knockout mice relative to wildtype controls
Exp Paradigm: Western blot: glua2-ps880
 Western blot
 Adult
Gene expression1
Decreased
Description: Decreased level of gababeta3 in striatum of grip1/2 double knockout mice relative to wildtype controls
Exp Paradigm: Western blot: gababeta3
 Western blot
 Adult
Size/growth1
 No change
 Body weight measurement
 2-5 months
Anxiety1
 No change
 Elevated plus maze test
 2 months
Gene expression1
 No change
 Western blot
 Adult
Protein phosphorylation1
 No change
 Western blot
 Adult
Targeted expression1
 No change
 Western blot
 Adult
General locomotor activity1
 No change
 Open field test
 2 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 3 months
Reproductive function1
 No change
 General observations
 2-5 months
Olfaction1
 No change
 Olfactory discrimination test
 5 months
Aggression1
 No change
 Resident-intruder test
 4 months
 Not Reported: Circadian sleep/wake cycle, Communications, Immune response, Learning & memory, Maternal behavior, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure





Download GRIP1's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
AGAP2 ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 116986 Q99490 Y2H; GST; IP/WB
Chan CB , et al. 2011
AR androgen receptor 367 P10275 Y2H; IP/WB
Irvine RA , et al. 1999
CREBBP (CBP) CREB binding protein 1387 Q92793 GST
Christakos S , et al. 2007
CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 1499 Q9WU82 Phenotypic enhancement; GST; IP/WB; High-throughput fluorescence polarization interaction analysis assay
Song LN and Gelmann EP 2005
CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 1499 Q9WU82 Phenotypic enhancement
Lee YH and Stallcup MR 2006
CTNND2 catenin (cadherin-associated protein), delta 2 1501 Q9UQB3 IP/WB
IP/WB; Co-localization
Silverman JB , et al. 2007
CTNND2 catenin (cadherin-associated protein), delta 2 114028 O35116 IP/WB
IP/WB; Co-localization
Silverman JB , et al. 2007
EFNB1 ephrin-B1 1947 P98172 Y2H; IP/WB
Brckner K , et al. 1999
ESR2 estrogen receptor 2 (ER beta) 2100 F1D8N3 GST; IP/WB
Hershberger PA , et al. 2005
ESRRG estrogen-related receptor gamma 26381 P62509 IP/WB
Hirvonen J , et al. 2010
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP; RNA immunoprecipitation (RIP)
Ascano M Jr , et al. 2012
FNTB Protein farnesyltransferase subunit beta 100529261 P49356 IP; LC-MS/MS
Huttlin EL , et al. 2015
GPHN gephyrin 10243 Q9NQX3 IP/WB; GST
Yu W , et al. 2008
GPR37 G protein-coupled receptor 37 (endothelin receptor type B-like) 2861 O15354 Y2H
Dutta P , et al. 2014
IRF3 interferon regulatory factor 3 3661 Q14653 Y2H; IP/WB
Reily MM , et al. 2005
Merm1 Ribosome biogenesis methyltransferase WBSCR22 114049 O43709 IP/WB
Jangani M , et al. 2014
PICK1 protein interacting with PRKCA 1 9463 Q9NRD5 IP/WB
Lu W and Ziff EB 2005
PPARG peroxisome proliferator-activated receptor gamma 5468 P37231 IP/WB; GST
Yang W , et al. 2000
PRKD2 protein kinase D2 25865 Q9BZL6 Y2H
Colland F , et al. 2004
PRLHR prolactin releasing hormone 51052 P81277 IP/WB
Lin SH , et al. 2001
PSMB9 proteasome (prosome, macropain) subunit, beta type, 9 5698 P28065 Y2H; GST; IP/WB
Zhang H , et al. 2006
RXRA retinoid X receptor, alpha 6256 F1D8Q5 IP/WB; GST
Yang W , et al. 2000
SMAD3 SMAD family member 3 4088 P84022 IP/WB
Li G , et al. 2006
TR-B thyroid hormone receptor, beta 7068 P10828 IP/WB; Y2H
Tagami T , et al. 1998
VDR vitamin D (1,25- dihydroxyvitamin D3) receptor 7421 P11473 GST; IP/WB
Ismail A , et al. 2004
ALS2 amyotrophic lateral sclerosis 2 (juvenile) homolog (human) 74018 Q920R0 IP/WB; GST
Lai C , et al. 2006
BRCA2 breast cancer 2 12190 P97929 IP/WB
Shin S and Verma IM 2003
CALCOCO1 calcium binding and coiled coil domain 1 67488 Q8CGU1 GST; IP/WB
Kim JH , et al. 2006
CARM1 coactivator-associated arginine methyltransferase 1 59035 Q9WVG6 Y2H; IP/WB
Chen D , et al. 1999
CDK9 cyclin-dependent kinase 9 1025 P50750 IP; MS; Dexamethasone assay
Dobrovolna J , et al. 2011
CREB1 cAMP responsive element binding protein 1 1385 P16220 IP/WB
Hoang T , et al. 2013
CSNK2A1 casein kinase 2, alpha 1 polypeptide 1457 P68400 IP; MS; Dexamethasone assay
Dobrovolna J , et al. 2011
CSPG4 chondroitin sulfate proteoglycan 4 81651 Q00657 Y2H; IP/WB
Stegmller J , et al. 2002
CTNND2 catenin (cadherin associated protein), delta 2 18163 O35927 IP/WB
Poore CP , et al. 2010
EFNA5 ephrin-A5 1946 P52803 GST; IP/WB
Kressler D , et al. 2007
EHMT2 euchromatic histone lysine N-methyltransferase 2 110147 Q9Z148 IP/WB
Lee DY , et al. 2006
EP300 E1A binding protein p300 2033 Q9Y6B2 IP/WB
Lee YH , et al. 2002
ESR1 estrogen receptor 1 2099 P03372 GST
Webb P , et al. 1998
FLI-I Protein flightless-1 homolog 9606 Q13045 IP/WB
Lee YH , et al. 2004
GRIK2 glutamate receptor, ionotropic, kainate 2 (beta 2) 14806 P39087 GST
Hirbec H , et al. 2002
GRIP1 glutamate receptor interacting protein 1 84016 P97879 GST; IP/WB
Liu PY , et al. 2006
HDAC1 histone deacetylase 1 3065 Q13547 IP/WB
Liu PY , et al. 2006
HIST1H3A histone cluster 1, H3a 8350 P68431 IP/WB
Ananthanarayanan M , et al. 2004
IL6 interleukin 6 (interferon, beta 2) 3569 B4DVM1 Luciferase reporter assay; ChIP
Verhoog NJ , et al. 2011
JUN Jun oncogene 16476 P05627 IP/WB; GST
Teyssier C , et al. 2003
KIF3A kinesin family member 3A 16568 P28741 IP/WB
Lin Y , et al. 2012
KIF5 kinesin family member 5A 16572 P33175 Y2H; IP/WB
Setou M , et al. 2002
LRRFIP1 leucine rich repeat (in FLII) interacting protein 1 9208 E9PGZ2 IP/WB
Lee YH and Stallcup MR 2006
NETO2 neuropilin (NRP) and tolloid (TLL)-like 2 74513 Q8BNJ6 IP/WB; GST
Tang M , et al. 2012
NR1I2 nuclear receptor subfamily 1, group I, member 2 18171 O75469 M2H; IP/WB
Ding X , et al. 2006
NR2C1 nuclear receptor subfamily 2, group C, member 1 22025 Q505F1 IP/WB; GST
Gupta P , et al. 2007
NR2F1 nuclear receptor subfamily 2, group F, member 1 7025 P10589 Y2H; Beta-galactosidase filter assay
Sugiyama T , et al. 2000
NR3C1 nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) 2908 F1D8N4 IP/WB
Li G , et al. 2006
PIAS2 protein inhibitor of activated STAT 2 17344 Q8C5D8 IP/WB; GST
Kotaja N , et al. 2002
PLAGL1 pleiomorphic adenoma gene-like 1 22634 Q9JLQ4 Y2H
Huang SM and Stallcup MR 2000
PML promyelocytic leukemia 5371 P29590 IP/WB; GST
Liu ST , et al. 2013
PRKACA protein kinase, cAMP-dependent, catalytic, alpha 5566 P17612 IP/WB
Hoang T , et al. 2013
PRMT1 protein arginine methyltransferase 1 60421 Q63009 GST; IP/WB
Lee DY , et al. 2007
Rbfox1 RNA binding protein, fox-1 homolog (C. elegans) 1 268859 Q9JJ43 HITS-CLIP
Weyn-Vanhentenryck SM , et al. 2014
RXRB retinoid X receptor beta 20182 P28704 M2H
Osburn DL , et al. 2001
Sec8 exocyst complex component 4 60412 Q96A65 IP/WB
Mao L , et al. 2010
SHANK2 SH3/ankyrin domain gene 2 210274 Q80Z38 IP/WB
Uemura T , et al. 2004
SLC30A9 solute carrier family 30 (zinc transporter), member 9 109108 Q5IRJ6 GST; Y2H
Chen YH , et al. 2005
SNAP25 synaptosomal-associated protein 25 20614 P60879 IP/WB; GST
Selak S , et al. 2009
TRIM24 tripartite motif-containing 24 21848 Q64127 Y2H; IP/WB
Teyssier C , et al. 2005
UBC ubiquitin C 7316 P63279 GST; IP/WB
Hoang T , et al. 2004
UBE2I ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast) 7329 P63279 GST; IP/WB
Chang YL , et al. 2007
CDH2 cadherin 2 12558 P15116 Y2H; IP/WB
Heisler FF , et al. 2014
EFNB2 ephrin B2 13642 Q4FJM3 GST; Y2H; IP/WB
Torres R , et al. 1999
GluA2 Glutamate receptor 2 14800 P23819 Y2H; IP/WB
Heisler FF , et al. 2014
GluR3 glutamate receptor, ionotropic, AMPA3 (alpha 3) 53623 Q9Z2W9 Y2H; GST
Hirbec H , et al. 2002
GluR4a glutamate receptor, ionotropic, AMPA4 (alpha 4) 14802 Q9Z2W8 Y2H; GST
Hirbec H , et al. 2002
GluR6 glutamate receptor, ionotropic, kainate 2 (beta 2) 14806 P39087 Y2H; GST
Hirbec H , et al. 2002
GluR7a glutamate receptor, ionotropic, kainate 3 14807 B1AS29 Y2H; GST
Hirbec H , et al. 2002
GluR7b glutamate receptor, ionotropic, kainate 3 14807 B1AS29 Y2H; GST
Hirbec H , et al. 2002
GRIK1 glutamate receptor, ionotropic, kainate 1 29559 P22756 Y2H; GST
Hirbec H , et al. 2003
GRIP1 glutamate receptor interacting protein 1 74053 Q925T6 GST; IP/WB
Liu PY , et al. 2006
GRIPAP1 GRIP1 associated protein 1 116493 Q9JHZ4 Y2H
Ye B , et al. 2000
NUMBL numb homolog (Drosophila)-like 292732 A1L1I3 Y2H
Ye B , et al. 2000
PPFIA1 protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 1 293645 D3ZZ81 Y2H; IP/WB; GST
Wyszynski M , et al. 2002
ZDHHC5 zinc finger, DHHC-type containing 5 362156 Q2THW7 IP/WB; GST
Thomas GM , et al. 2012
ZDHHC8 zinc finger, DHHC-type containing 8 303796 Q2THW6 IP/WB; GST
Thomas GM , et al. 2012

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