HGNC Approved Gene Symbol: GRIP1
Cytogenetic location: 12q14.3 Genomic coordinates (GRCh38): 12:66,347,431-67,069,338 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q14.3 | Fraser syndrome 3 | 617667 | Autosomal recessive | 3 |
The recruitment of signaling molecules to the plasma membrane is a prerequisite for the functioning of various signaling cascades. Correct localization within the plasma membrane is equally important, as the membrane itself is highly organized into lipid domains that provide subcompartments. These small (less than 100 nm) membrane domains, called rafts, are enriched in sphingolipids and cholesterol and can incorporate GPI-anchored proteins, specific transmembrane proteins, and doubly acylated proteins like tyrosine kinases of the Src family. Rafts have been proposed to function as platforms for the localized concentration and activation of signaling molecules. Transmembrane ephrin B proteins have important roles during embryonic patterning as ligands for Eph receptor tyrosine kinases and presumably as signal-transducing receptor-like molecules. Ephrin B1 (EFNB1; 300035) is localized in raft microdomains. Using a yeast 2-hybrid system to identify proteins that bind to the cytoplasmic domain of EFNB1, Bruckner et al. (1999) isolated a partial human fetal brain cDNA encoding GRIP1. The predicted GRIP1 protein, which lacks the N-terminal region, contains a partial PDZ3 domain and intact PDZ4 through PDZ7 domains. GRIP1 binds to the C terminus of EFNB1, which contains a PDZ-binding consensus motif. In situ hybridization of embryonic day 17 (E17) rat embryos showed that Grip1 is expressed relatively homogeneously and strongly throughout most regions of the nervous system. Grip1 was expressed at very low levels in many nonneuronal tissues of embryonic day 17 rat, with the highest levels found in nasal cavities and major blood vessels. Coimmunoprecipitation analysis demonstrated that Grip1 and Efnb1 interact in embryonic day 14 mouse embryos. Bruckner et al. (1999) found that GRIP1 is recruited into rafts through association with EFNB1. In addition, a GRIP1-associated serine/threonine kinase activity was recruited into EFNB1/GRIP1 complexes. Bruckner et al. (1999) suggested that GRIP proteins provide a scaffold for the assembly of a multiprotein signaling complex downstream of ephrin B ligands.
Setou et al. (2002) demonstrated that an AMPA receptor (AMPAR) subunit, GluR2-interacting protein (GRIP1), can directly interact and steer kinesin heavy chains to dendrites as a motor for AMPARs. As would be expected if this complex is functional, both gene targeting and dominant-negative experiments of heavy chains of mouse kinesin showed abnormal localization of GRIP1. Moreover, expression of the kinesin-binding domain of GRIP1 resulted in accumulation of the endogenous kinesin predominantly in the somatodendritic area. This pattern was different from that generated by overexpression of the kinesin-binding scaffold protein JSAP1 (605431), which occurred predominantly in the somatoaxon area. Setou et al. (2002) concluded that directly binding proteins can determine the traffic direction of a motor protein.
Contractor et al. (2002) reported that mossy fiber long-term potentiation was reduced by perfusion of postsynaptic neurons with peptides and antibodies that interfere with binding of EphB receptor tyrosine kinases to the PDZ protein GRIP1. Mossy fiber long-term potentiation was also reduced by extracellular application of soluble forms of beta-ephrins, which are normally membrane-anchored presynaptic ligands for the EphB receptors. The application of soluble ligands for presynaptic ephrins increased basal excitatory transmission and occluded both tetanus and forskolin-induced synaptic potentiation. Contractor et al. (2002) concluded that the PDZ interactions in postsynaptic neuron and transsynaptic interactions between postsynaptic EphB receptors and presynaptic beta-ephrins are necessary for the induction of mossy fiber long-term potentiation.
At rat cerebellar parallel fiber-stellate cell synapses, Ca(2+) influx through Glur2 (GRIA2; 138247)-lacking AMPARs drives incorporation of Ca(2+)-impermeable Glur2-containing AMPARs, generating rapid changes in excitatory postsynaptic current properties. Liu and Cull-Candy (2005) found that repetitive synaptic activity triggered loss of Ca(2+)-permeable AMPARs by disrupting their interaction with Grip. Pick (PICK1; 605926) drove activity-dependent delivery of Ca(2+)-impermeable receptors into the synaptic membrane. Liu and Cull-Candy (2005) concluded that dynamic regulation of AMPARs by GRIP and PICK provides a mechanism for controlling Ca(2+) permeability of synaptic receptors.
In 2 unrelated male fetuses with typical features of Fraser syndrome (FRASRS3; 617667), Vogel et al. (2012) identified homozygosity for a splice site mutation in the GRIP1 gene (604597.0001). In addition, the consanguineous parents of a third male fetus with Fraser syndrome were found to be heterozygous for a 4-bp deletion in the GRIP1 gene (604597.0002); no DNA was available from the presumably homozygous fetus.
Bladt et al. (2002) found that elimination of the mouse Grip1 gene results in embryonic lethality. Null embryos developed abnormalities in the dermo-epidermal junction, resulting in extensive skin blistering around day 12 of embryonic life. Ultrastructural characterization of the blisters (or bullae) revealed cleavage of the dermo-epidermal junction below the lamina densa, an alteration reminiscent of the dystrophic form of human epidermolysis bullosa (226600). Blisters were also observed in the lateral ventricle of the brain and in the meninges covering the cerebral cortex. Thus, it appears that GRIP1 scaffolding protein is required for the formation and integrity of the dermo-epidermal junction and that PDZ domains are important in the organization of supramolecular structures essential for mammalian embryonic development.
Through the study of Grip1 -/- mice, Takamiya et al. (2004) found that loss of the Grip1 protein leads to the formation of subepidermal hemorrhagic blisters, renal agenesis, syndactyly or polydactyly, and permanent fusion of eyelids (cryptophthalmos). Similar malformations are characteristic of individuals with Fraser syndrome (see 219000) and animal models of the human disorder, such as mice carrying the 'blebbed' mutation (bl) in the Fras1 gene (607830), which encodes an extracellular matrix protein. Grip1 can visibly interact with Fras1 and is required for the localization of Fras1 to the basal side of cells. In one animal model of Fraser syndrome, the 'eye-blebs' (eb) mouse, Grip1 is disrupted by a deletion of 2 coding exons. From their data, Takamiya et al. (2004) concluded that Grip1 is required for normal cell-matrix interactions during early embryonic development and that inactivation of Grip1 causes Fraser syndrome-like defects in mice. Kiyozumi et al. (2006) showed that eb/eb mice had reduced localization of Fras1, Frem1 (608944), and Frem2 (608945) to epidermal basement membranes.
In 2 unrelated male fetuses with typical features of Fraser syndrome (FRASRS3; 617667), Vogel et al. (2012) identified homozygosity for a splice site mutation (c.2113+1G-C, NM_201150.3) in intron 17 of the GRIP1 gene, predicted to cause skipping of exon 17. The unaffected consanguineous parents from both families were heterozygous for the splice site mutation, which was not found in multiple mutation and SNP databases or in more than 40 exomes sequenced by the authors. Analysis of GRIP1 expression in 1 set of parents revealed a 374-bp (wildtype) mRNA product as well as a 234-bp fragment lacking exon 17, confirming that the splice site mutation causes a frameshift resulting in a premature termination codon.
In the unaffected consanguineous parents of a male fetus with typical features of Fraser syndrome (FRASRS3; 617667), Vogel et al. (2012) identified heterozygosity for a 4-bp deletion (c.1181_1184delAAGA, NM_201150.3) in exon 10 of the GRIP1 gene, predicted to cause a frameshift and premature termination codon. The fetus was presumed to be homozygous for the deletion, although no DNA was available.
Bladt, F., Tafuri, A., Gelkop, S., Langille, L., Pawson, T. Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1. Proc. Nat. Acad. Sci. 99: 6816-6821, 2002. [PubMed: 11983858] [Full Text: https://doi.org/10.1073/pnas.092130099]
Bruckner, K., Pablo Labrador, J., Scheiffele, P., Herb, A., Seeburg, P. H., Klein, R. EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron 22: 511-524, 1999. [PubMed: 10197531] [Full Text: https://doi.org/10.1016/s0896-6273(00)80706-0]
Contractor, A., Rogers, C., Maron, C., Henkemeyer, M., Swanson, G. T., Heinemann, S. F. Trans-synaptic Eph receptor-ephrin signaling in hippocampal mossy fiber LTP. Science 296: 1864-1869, 2002. [PubMed: 12052960] [Full Text: https://doi.org/10.1126/science.1069081]
Kiyozumi, D., Sugimoto, N., Sekiguchi, K. Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects. Proc. Nat. Acad. Sci. 103: 11981-11986, 2006. [PubMed: 16880404] [Full Text: https://doi.org/10.1073/pnas.0601011103]
Liu, S. J., Cull-Candy, S. G. Subunit interaction with PICK and GRIP controls Ca(2+) permeability of AMPARs at cerebellar synapses. Nature Neurosci. 8: 768-775, 2005. [PubMed: 15895086] [Full Text: https://doi.org/10.1038/nn1468]
Setou, M., Seog, D.-H., Tanaka, Y., Kanai, Y., Takei, Y., Kawagishi, M., Hirokawa, N. Glutamate receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417: 83-87, 2002. [PubMed: 11986669] [Full Text: https://doi.org/10.1038/nature743]
Takamiya, K., Kostourou, V., Adams, S., Jadeja, S., Chalepakis, G., Scambler, P. J., Huganir, R. L., Adams, R. H. A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1. Nature Genet. 36: 172-177, 2004. [PubMed: 14730302] [Full Text: https://doi.org/10.1038/ng1292]
Vogel, M. J., van Zon, P., Brueton, L., Gijzen, M., van Tuil, M. C., Cox, P., Schanze, D., Kariminejad, A., Ghaderi-Sohi, S., Blair, E., Zenker, M., Scambler, P. J., Ploos van Amstel, H. K., van Haelst, M. M. Mutations in GRIP1 cause Fraser syndrome. J. Med. Genet. 49: 303-306, 2012. [PubMed: 22510445] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100590]