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GRIP1
glutamate receptor interacting protein 1
The GRIP1 gene provides instructions for a protein vital for cellular organisation and the correct transport of other proteins within the cell, particularly in development and nervous system function. The GRIP1 gene encodes the glutamate receptor interacting protein 1, which acts as a molecular transporter.
GRIP1 is located on the long (q) arm of chromosome 12, at band 12q14.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The GRIP1 gene is responsible for producing the Glutamate Receptor Interacting Protein 1, an essential component for maintaining cellular organisation. This protein helps to ensure that other proteins are delivered to their appropriate cellular destinations. This transport function is critical for various biological processes, including tissue development and neurological function.
The GRIP1 protein's role in guiding proteins to specific sites underscores its importance in the proper formation and functioning of several bodily systems.
What the gene does
The GRIP1 protein functions as a molecular escort, facilitating the transport of specific proteins to their designated cellular compartments. A key partnership involves GRIP1 transporting proteins derived from the FRAS1 and FREM2 genes. These proteins subsequently assemble into the FRAS/FREM complex, which is integral to the structure and function of basement membranes-thin, supportive layers found in many tissues.
Within basement membranes, the FRAS/FREM complex helps anchor the skin's layers and is involved in the organised development of organs such as the kidneys. Additionally, GRIP1 is crucial in the brain, where it moves necessary proteins to the synapses, which are the junctions between nerve cells. This transport mechanism supports effective cell-to-cell communication and may also contribute to the development of neurons.
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Chromosome location
The GRIP1 gene is situated on chromosome 12 at position 12q14.3. This specific genomic address indicates its location on the long arm of chromosome 12. The gene provides the genetic blueprint for a protein composed of 1128 amino acids.
Protein structure
The GRIP1 protein comprises several distinct functional regions, including multiple PDZ domains. These include PDZ 1 (amino acids 53-136), PDZ 2 (amino acids 150-238), PDZ 3 (amino acids 252-336), PDZ 4 (amino acids 472-561), PDZ 5 (amino acids 573-658), PDZ 6 (amino acids 673-755), and PDZ 7 (amino acids 1004-1086). These PDZ domains are protein-binding modules often involved in assembling multi-protein complexes and localising proteins. The protein also contains several disordered regions, including stretches at amino acids 754-798, 935-981, and 1093-1128, which typically allow for flexibility and interaction with various partners.
Key variants
Genetic variations within the GRIP1 gene can impact its ability to produce a functional protein or affect the protein's overall activity. These changes, known as pathogenic variants, can alter the protein's structure, thereby disrupting its critical role in cellular transport and organisation. The specific effects of a variant depend on its nature and location within the gene.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.30T>A | p.Cys10Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fraser syndrome 3 |
g.(?_66838344)_(67072684_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_66859035)_(66859222_?)del | - | Pathogenic | ★☆☆☆ | not provided |
g.(?_67072610)_(67072684_?)del | - | Pathogenic | ★☆☆☆ | not provided |
c.1633C>T | p.Arg545Ter | Pathogenic | ★☆☆☆ | not provided |
c.2749del | p.Arg917fs | Pathogenic | ★☆☆☆ | not provided |
c.2775_2776del | p.Leu926fs | Pathogenic | ★☆☆☆ | not provided |
c.2885del | p.Pro962fs | Pathogenic | ★☆☆☆ | not provided |
c.505G>T | p.Gly169Ter | Pathogenic | ★☆☆☆ | not provided |
c.672_675del | p.Lys224fs | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the GRIP1 gene have been linked to several health conditions, primarily affecting development. A small percentage of cases of Fraser syndrome are associated with GRIP1 variants, which is characterised by developmental abnormalities affecting the eyes, skin, and kidneys. GRIP1 variants have also been associated with coloboma and congenital anomalies of the kidney and urinary tract.
No disease links recorded for this gene in our reference set.
UK clinical status
The GRIP1 gene is currently assessed by the NHS Genomic Medicine Service and is included in several R-panels. It is classified as green for Anophthalmia or microphthalmia, CAKUT (Congenital Anomalies of the Kidney and Urinary Tract), Deafness and congenital structural abnormalities, Limb disorders, Structural eye disease (R36), Unexplained kidney failure in young people, and Unexplained young onset end-stage renal disease - additional genes. It is also green on the Foetal anomalies panel (R21).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the GRIP1 protein?
The GRIP1 protein is primarily responsible for transporting other proteins to their correct locations within cells, which is crucial for cellular organisation, tissue development, and communication between nerve cells.
Which conditions are associated with changes in the GRIP1 gene?
Pathogenic variants in the GRIP1 gene are associated with a small percentage of Fraser syndrome cases, which involves developmental issues affecting the eyes, skin, and kidneys. It is also linked to coloboma and congenital anomalies of the kidney and urinary tract.
How does GRIP1 affect the FRAS/FREM complex?
GRIP1 transports proteins from the FRAS1 and FREM2 genes, enabling them to form the FRAS/FREM complex. This complex is vital for the structure of basement membranes and for anchoring skin layers.
References
- Schanze D, Kayserili H, Satkın BN. Fraser syndrome due to mutations in GRIP1--clinical phenotype in two families and expansion of the mutation spectrum. American journal of medical genetics. Part A. 2014. PMID: 24357607
- Heisler FF, Lee HK, Gromova KV. GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites. Proceedings of the National Academy of Sciences of the United States of America. 2014. PMID: 24639525
- Vogel MJ, van Zon P, Brueton L. Mutations in GRIP1 cause Fraser syndrome. Journal of medical genetics. 2012. PMID: 22510445
- Short K, Wiradjaja F, Smyth I. Let's stick together: the role of the Fras1 and Frem proteins in epidermal adhesion. IUBMB life. 2007. PMID: 17654118
- Takamiya K, Kostourou V, Adams S. A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1. Nature genetics. 2004. PMID: 14730302
- Dong H, Zhang P, Song I. Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999. PMID: 10436050