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C9orf72 - C9orf72-SMCR8 complex subunit (human)

Gene
Symbol
Dates
  • Create:
    2016-09-14
  • Modify:
    2025-01-29
Description
The protein encoded by the C9orf72 gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]
Enables GTPase activator activity and small GTPase binding activity. Contributes to guanyl-nucleotide exchange factor activity. Involved in several processes, including axon extension; regulation of organelle organization; and stress granule assembly. Located in several cellular components, including axon; cytoplasmic ribonucleoprotein granule; and vacuole. Part of guanyl-nucleotide exchange factor complex. Is active in presynaptic cytosol. Implicated in frontotemporal dementia and/or amyotrophic lateral sclerosis 1.

The C9orf72 gene provides instructions for making a protein that is found in various tissues. The protein is abundant in nerve cells (neurons) in the outer layers of the brain (cerebral cortex) and in specialized neurons in the brain and spinal cord that control movement (motor neurons). The C9orf72 protein is thought to be located at the tip of the neuron in a region called the presynaptic terminal. This area is important for sending and receiving signals between neurons.

The C9orf72 protein likely plays a role in many processes involving the chemical cousin of DNA, known as RNA. This protein is thought to influence the production of RNA from genes, the production of proteins from RNA, and the transport of RNA within the cell.

The C9orf72 gene contains a segment of DNA made up of a series of six DNA building blocks (nucleotides), four guanines followed by two cytosines (written as GGGGCC). This segment (known as a hexanucleotide repeat) can occur once or be repeated multiple times in a row; estimates suggest repeats of up to 30 times have no negative effect on gene function.

1 Names and Identifiers

1.1 Synonyms

  • ALSFTD
  • DENND9
  • DENNL72
  • FTDALS
  • FTDALS1
  • guanine nucleotide exchange factor C9orf72
  • guanine nucleotide exchange C9orf72
  • protein C9orf72

1.1.1 MeSH Entry Terms

  • Chromosome 9 Open Reading Frame 72 Protein
  • Guanine Nucleotide Exchange Factor C9orf72

1.2 Other Identifiers

1.2.1 HGNC ID

1.2.2 Ensembl ID

1.2.3 Alliance Gene ID

1.2.4 Bgee Gene ID

1.2.5 GenCC ID

1.2.6 KEGG Gene

1.2.7 MIM Number

1.2.8 NCI Thesaurus Code

1.2.9 Open Targets ID

1.2.10 PharmGKB ID

1.2.11 Pharos Target

1.2.12 VEuPathDB ID

1.2.13 Wikidata

3 Proteins

3.1 Protein Function

Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PMID: 27103069, PMID: 27193190, PMID: 27617292, PMID: 28195531, PMID: 32303654). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PMID: 27103069). The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and modulating its protein kinase activity (PMID: 27617292). As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro (PMID: 32303654). Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ULK1/ATG1 kinase complex to the phagophore which leads to autophagosome formation (PMID: 27334615). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PMID: 27559131). Plays a role in endosomal trafficking (PMID: 24549040). May be involved in regulating the maturation of phagosomes to lysosomes (By similarity). Promotes the lysosomal localization and lysosome-mediated degradation of CARM1 which leads to inhibition of starvation-induced lipid metabolism (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation (PMID: 27723745). This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to CFL1/cofilin activation (PMID: 27723745). Positively regulates axon extension and axon growth cone size in spinal motor neurons (PMID: 27723745). Required for SMCR8 protein expression and localization at pre- and post-synaptic compartments in the forebrain, also regulates protein abundance of RAB3A and GRIA1/GLUR1 in post-synaptic compartments in the forebrain and hippocampus (By similarity). Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity (By similarity).

Regulates stress granule assembly in response to cellular stress.

Does not play a role in regulation of stress granule assembly in response to cellular stress.

3.2 Protein Isoforms

Isoform
Isoform 1
UniProt ID
RefSeq Accession
Isoform
Isoform 1
UniProt ID
RefSeq Accession
Isoform
Isoform 2
UniProt ID
RefSeq Accession

3.3 Protein 3D Structures

3.3.1 PDB Structures

3.3.2 NCBI Protein Structures

3.3.3 AlphaFold Structures

Highly accurate protein structure prediction with AlphaFold. Nature. 2021 Aug;596(7873):583-589. DOI:10.1038/s41586-021-03819-2. PMID:34265844; PMCID:PMC8371605

3.4 Protein Targets

4 BioAssays

4.1 RNAi BioAssays

5 Diseases and Phenotypes

5.1 GHR Health Conditions

5.2 KEGG Diseases

5.3 OMIM Phenotypes

5.4 MedGen Diseases

5.5 Gene-Disease Associations

6 Interactions and Pathways

6.1 Chemical-Gene Interactions

6.2 Interactions

6.3 Pathways

7 Cell Lines

8 Expression

9 Target Development Level

10 Literature

10.1 Consolidated References

10.2 NLM Curated PubMed Citations

10.3 Gene-Chemical Co-Occurrences in Literature

10.4 Gene-Gene Co-Occurrences in Literature

10.5 Gene-Disease Co-Occurrences in Literature

11 Patents

11.1 Gene-Chemical Co-Occurrences in Patents

11.2 Gene-Gene Co-Occurrences in Patents

11.3 Gene-Disease Co-Occurrences in Patents

12 Classification

12.1 Gene Family

12.2 MeSH Tree

12.3 NCI Thesaurus Tree

12.4 Gene Ontology: Biological Process

12.5 Gene Ontology: Cellular Component

12.6 Gene Ontology: Molecular Function

13 Information Sources

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  6. BioGRID
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  7. STRING: functional protein association networks
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    http://www.dgidb.org/downloads
  10. Open Targets
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    C9orf72
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  17. NCBI MedGen
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  18. NCBI Structure
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  21. PharmGKB
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  22. Pharos
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  23. RCSB Protein Data Bank (RCSB PDB)
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  24. Swiss Institute of Bioinformatics Bgee
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  28. Gene Ontology (GO)
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  29. AlphaFold DB
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    https://alphafold.ebi.ac.uk/faq
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