Function |
Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy |
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, Note=Detected in the cytoplasm of neurons from brain tissue (PubMed:21944778), Detected in the nucleus in fibroblasts (PubMed:21944779), During corticogenesis, transitions from being predominantly cytoplasmic to a more even nucleocytoplasmic distribution (By similarity), SUBCELLULAR LOCATION: Isoform 1: Perikaryon, Cell projection, dendrite, Note=Expressed diffusely throughout the cytoplasm and dendritic processes of cerebellar Purkinje cells, Also expressed diffusely throughout the cytoplasm of spinal motor neurons, SUBCELLULAR LOCATION: 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). |
Database Links |
HGNC: 28337 OMIM: 105550 KEGG: hsa:203228 STRING: 9606.ENSP00000369339 UniGene: Hs.493639 |