page_title: Glutamate receptor-interacting protein
section_title: Role of GRIP1 in Fraser syndrome
hierarchical_section_title: Glutamate receptor-interacting protein / Role of GRIP1 in Fraser syndrome
caption_attribution_description: English: This diagram depicts the role GRIP1 plays in localizing extra-cellular matrix proteins Fras1 and Frem2 at the dermo-epidermal junction.
context_page_description: Glutamate receptor-interacting protein refers to either a family of proteins that bind to the glutamate receptor or specifically to the GRIP1 protein within this family. Proteins in the glutamate receptor-interacting protein family have been shown to interact with GluR2, a common subunit in the AMPA receptor. This subunit also interacts with other proteins such as protein interacting with C-kinase1 and N-ethylmaleimide-sensitive fusion protein. Studies have begun to elucidate its function; however, much is still to be learned about these proteins.
context_section_description: Mutations to GRIP1 play a role in less than 10% of confirmed cases of the group of congenital defects known as Fraser syndrome. Using immunofluorescence, it has been shown that GRIP1 is found in several kinds of embryonic tissues, including the GI tract, ureter buds, skin and oral and nasal cavities. GRIP1 is also essential for proper function and structure of the dermo-epidermal junction. In mouse models, knocking out GRIP1 protein leads to several deformities that begin in embryo. These deformities include subepidermal hemorrhagic blistering, renal agenesis, syndactylism, polydactylism and cryptopthalmos. One study has shown that complete knock-out of GRIP1 leads to the absence of kidneys. Another study shows blistering of embryonic tissue that GRIP1 is expressed in by day 12 of embryonic life in mice.
  The mechanism of GRIP1 in Fraser syndrome is found in the interaction GRIP1 has with the proteins Fras1 and Frem2. Fras1 and Frem2 are extracellular membrane proteins necessary for proper basement membrane function as well as morphogenesis. GRIP1 plays a vital role in localizing Fras1 to the basal surface of epidermal cells as well as localizing Frem2. Knocking out the GRIP1 protein or mutating it leads to poor expression of Fras1 and Frem2. GRIP1 specifically binds with Fras1 through a PDZ motif located on Fras1. Frem2 also has a PDZ domain, although the interaction between GRIP1 and Frem2 is unclear. In one case of Fraser syndrome, GRIP1 lacked PDZ domains 6 and 7. Only the first four PDZ domains of the seven PDZ domains GRIP1 has are required for binding with Fras1, indicating additional mechanisms and proteins GRIP1 interacts with that could lead to Fraser syndrome when mutated. Other mutations in GRIP1 that lead to Fraser syndrome include nonsense mutations, frameshift mutations, splice site mutations, a genome deletion and a deletion of exon 18 of the GRIP1 gene.
caption: This diagram depicts the role GRIP1 plays in localizing extra-cellular matrix proteins Fras1 and Frem2 at the dermo-epidermal junction.
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