Function
Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy. 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. The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and modulating its protein kinase activity. Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ATG1/ULK1 kinase complex to the phagophore which leads to autophagosome formation. Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates. Plays a role in endosomal trafficking. May be involved in regulating the maturation of phagosomes to lysosomes. Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation. This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to cofilin activation. Positively regulates axon extension and axon growth cone size in spinal motor neurons. Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity.; 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.
Gene References into Functions
- Review: Drosophila has been widely used to model G4C2 repeat RNA and dipeptide repeat protein toxicity. Overexpression of disease molecules in flies has revealed important molecular insights. These have been validated and further explored in human neurons differentiated from induced pluripotent stem cells (iPSCs), a disease-relevant model in which expanded G4C2 repeats are expressed in their native molecular context. PMID: 29729808
- Amyotrophic lateral sclerosis patients with C9ORF72 repeat expansions accumulate symmetric arginine demethylated proteins which co-localize with p62. PMID: 30022074
- This study demonstrated that C9orf72 RE is not genetically associated to MS spectrum. PMID: 30099204
- Results found that in sodium or potassium salt solutions, single-stranded d(C2G4)n within C9orf72 gene fold to form G-quadruplexes. Especially under slightly acidic conditions, d(C2G4)n oligonucleotides fold to form a distinctive higher order structure whose most striking feature is an "inverted" circular dichroism spectrum, which is distinguishable from the spectrum of the left handed DNA double-helix, Z-DNA. PMID: 29912891
- repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats PMID: 28677678
- Review discussing the discovery of an intronic (G4C2)*(G2C4) expansion causing the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This discovery linked ALS with a clinically distinct form of dementia and a larger group of microsatellite repeat diseases, and catalyzed basic and translational research. PMID: 29703376
- G4C2 hexanucleotide repeat expansions in the C9orf72 gene seem to be the cause of numerous cases of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). PMID: 29449030
- C9orf72 hexanucleotide repeat expansion (RE) mutation in amyotrophic lateral sclerosis (ALS) patients of 2 distinct origins, Ashkenazi and North Africa Jews. PMID: 29352617
- C9orf72 disease is clinically heterogeneous and without evident imaging markers PMID: 29441485
- that the overall frequency of C9orf72-positive cases in Greek FTD is high, comparable to Greek ALS, similar to some Western European, but significantly higher than some Mediterranean FTD populations PMID: 29166782
- The C9orf72 repeat expansion linked to aggressive disease in male patients with spinal-onset ALS. PMID: 27739539
- The genetic mutations of C9ORF72 caused amyotrophic lateral sclerosis. PMID: 29478603
- Findings provide evidence that C9orf72 poly GA is a key mediator of cytotoxicity and that cross-talk between DPR proteins likely modifies their pathogenic status in C9ALS/FTD. PMID: 28973350
- DNA methylation analysis of C9orf72 patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset. PMID: 28439722
- This study demonstrated that poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients. PMID: 28409281
- A pathological repeat expansion in the C9orf72 gene (50 repeats) was found in a patient with mild diffuse brain atrophy and type 2 progressive apraxia of speech. This is the first described association of this gene with type 2 progressive speech apraxia. PMID: 27166164
- The association of the C9orf72 repeat expansion with ALS and frontotemporal degeneration. PMID: 27713094
- in common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms PMID: 28689190
- Mutations in the footprinted region of Nup54 polymers blocked both polymerization and binding by the toxic proline:arginine poly-dipeptide suggesting that toxicity of the C9orf72 PRn poly-dipeptide results in part from its ability to lock the FG repeats of nuclear pore proteins in the polymerized state. PMID: 28069952
- DPR-mediated dysfunction of U2 snRNP could account for as much as approximately 44% of the mis-spliced cassette exons in C9ORF72 patient brains. PMID: 28614712
- C9ORF72 repeat expansion leads to the upregulation of GluA1 in motor neurons, that could lead to a potential pathogenic excitotoxic mechanism in amyotrophic lateral sclerosis patients. PMID: 29367641
- This study demonstrated that in ALS with cognition disorder has C9orf72 mutation. PMID: 28444446
- von Economo neuron density was reduced in sporadic behavioral variant frontotemporal dementia (bvFTD) cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion. PMID: 28482638
- The result of this study concluded that behavioral variant frontotemporal dementia patients carrying the C9ORF72 expansion may display more pronounced executive deficits together with less severe verbal memory impairment as compared to their non-carrier behavioral variant frontotemporal dementia counterparts. PMID: 28453474
- The C9orf72 hexanucleotide repeat was only found in humans, chimpanzees and gorillas, species with higher opposability indices PMID: 28010125
- the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival in amyotrophic lateral sclerosis PMID: 27936955
- toxic poly-dipeptides translated from C9orf72 may account for hereditary cases of amyotrophic lateral sclerosis and frontotemporal dementia PMID: 29045370
- For DNA, the data are consistent with TMPyP4 stacking on the terminal tetrads and intercalation. For RNA, the thermodynamics of the two binding modes are consistent with groove binding and intercalation. PMID: 29274339
- Demyelinating lesions might facilitate expressivity of C9orf72 expansion, through NF-kappaB activation. This plausible association may lead to the identification of a therapeutic target in this subgroup of C9orf72-amyotrophic lateral sclerosis patients. PMID: 29055436
- These findings suggest that the presence of a C9orf72 mutation does not influence the tau signature of ALS or ALSci. PMID: 28562075
- We created Smcr8 knockout mice and found that Smcr8 mutant cells exhibit impaired autophagy induction, which is similarly observed in C9orf72 knockdown cells. Mechanistically, SMCR8/C9ORF72 interacts with the key autophagy initiation ULK1 complex and regulates expression and activity of ULK1 PMID: 27617292
- Our study did not find any pathological C9ORF72 repeat expansions in two large groups of patients with disease and multiple system atrophy, suggesting that C9ORF72 expansions do not play a major role in the susceptibility to the wider spectrum of Parkinsonism. However, study identified a statistically significant association between number of repeats and age at onset in Parkinson's disease patients. PMID: 27473499
- Pathogenesis may occur either due to loss of function of the C9orf72 gene, or a toxic gain of function, via the production of repetitive sense and antisense RNA and/or repetitive dipeptide repeat proteins. Recently, mouse knockouts have suggested that a loss of function of C9orf72 alone is insufficient to lead to neurodegeneration, whilst overexpression of hexanucleotide DNA is sufficient in a wide range of model systems PMID: 28364657
- We review what has been published regarding C9orf72 repeat size as modifier for phenotypic characteristics. Conclusive evidence is lacking, partly due to the difficulties in accurately defining the exact repeat size and the presence of repeat variability due to somatic mosaicism PMID: 28319737
- C9orf72 patients had enhanced visual network functional connectivity versus sporadic-motor and sporadic-early cases PMID: 28666709
- C9orf72 and ATXN2 repeat expansions cause ataxia, dementia, and parkinsonism in a Guyana family. PMID: 28124431
- These findings indicate that tracking poly(GP) proteins in Cerebrospinal fluid could provide a means to assess target engagement of G4C2 repeat expansion RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers. PMID: 28356511
- Several family members of the patient suffered of atypical Parkinsonism, lateral amyotrophic sclerosis and dementia. We identified an abnormal hexanucleotide expansion in the C9orf72 gene in the proband. PMID: 29182198
- This study is an extensive characterization of induced pluripotent stem cells-derived motor neurons as cellular models of amyotrophic lateral sclerosis carrying C9orf72 hexanucleotide repeats. PMID: 27097283
- this implies that the difference between C9 hESCs and iPSCs may be crucial for investigating the neural phenotype of the C9/ALS-FTD disease, given that mutant hESCs are likely to present a more accurate and more severe phenotype than comparable iPSCs. PMID: 27773700
- The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)to combined ALS/FTD PMID: 28087719
- Together, these data implicate C9ORF72 GGGGCC expansion-mediated sequestration of hnRNP H as a significant contributor to neurodegeneration in C9 amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. PMID: 27623008
- The chromosome 9 open reading frame 72 (c9orf72) gene contains a hexanucleotide (GGGGCC) repeat expansion responsible for many cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). PMID: 28132891
- Psychotic symptoms in frontotemporal dementia with the C9orf72 gene expansion. PMID: 28116236
- Intronic repeat expansions in C9orf72 not observed in Iranian Parkinson's disease patients. PMID: 28365006
- Its mutation is a genetic cause of amyotrophic lateral sclerosis. PMID: 28222900
- Diffuse atrophy is a common underlying feature of disease associated with C9orf72 mutations. PMID: 27995069
- Its repeat expansion is a cause of amyotrophic lateral sclerosis in New Zealand. PMID: 27480424
- C9orf72 repeat expansions are not causally associated with dementia with lewy body. PMID: 27666590
- Repeat expansions in the chromosome 9 open reading frame 72 (C9orf72) gene have been recognized as a major contributor to amyotrophic lateral sclerosis. PMID: 28527524
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Involvement in disease
Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1)
Subcellular Location
Nucleus. Cytoplasm. Cytoplasm, P-body. Cytoplasm, Stress granule. Endosome. Lysosome. Cytoplasmic vesicle, autophagosome. Secreted. Cell projection, axon. Cell projection, growth cone. Perikaryon.; [Isoform 1]: Perikaryon. Cell projection, dendrite.; [Isoform 2]: Nucleus membrane; Peripheral membrane protein. Nucleus.
Tissue Specificity
Both isoforms are widely expressed, including kidney, lung, liver, heart, testis and several brain regions, such as cerebellum. Also expressed in the frontal cortex and in lymphoblasts (at protein level).
