|, chromosome 9 open reading frame 72, ALSFTD, FTDALS, FTDALS1, DENNL72, C9orf72-SMCR8 complex subunit, DENND9|
The protein is found in many regions of the brain, in the cytoplasm of neurons as well as in presynaptic terminals. Disease-causing mutations in the gene were first discovered by two independent research teams, led by Rosa Rademakers of Mayo Clinic and Bryan Traynor of the National Institutes of Health, and were first reported in October 2011. The mutations in C9orf72 are significant because it is the first pathogenic mechanism identified to be a genetic link between familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). It is the most common mutation identified that is associated with familial FTD and/or ALS.
Cytogenetic Location: 9p21.2
Molecular Location on chromosome 9: base pairs 27,546,546 to 27,573,866
The mutation of C9ORF72 is a hexanucleotide repeat expansion of the six letter string of nucleotides GGGGCC. In a person without the mutation, there are few repeats of this hexanucleotide, typically fewer than 20–30, but in people with the mutation, the repeat can occur in the order of hundreds. It is known that the mutation interferes with normal expression of the protein made by C9orf72, however the function of this protein remains speculative. There are two major theories about the way that the C9ORF72 mutation causes FTD and/or ALS. One theory is that accumulation of RNA in the nucleus and cytoplasm becomes toxic, and RNA binding protein sequestration occurs. The other is that the lack of half of the C9ORF72 protein (haploinsufficiency) in the body causes the diseases. Additionally, RNA transcribed from the C9ORF72 gene, containing expanded GGGGCC repeats, is translated through a non-ATG initiated mechanism, which is the same mechanism as other repeat disorders. This hexanucleotide varant of a trinucleotide repeat disorder produces five different dipeptides by RAN translation, these dipeptides aggregating to contribute to overall toxicity of the mutation. The GGGGCC repeat expansion in C9orf72 is also believed to compromise nucleocytoplasmic transport through several possible mechanisms.
The C9ORF72 mutation is the first mutation found to be a link between familial FTD and ALS. Numerous published studies have confirmed the commonality of the C9ORF72 repeat expansion in FTD and ALS, which are both diseases without cures that have affected millions of people. Frontotemporal dementia is the second most common form of early-onset dementia after Alzheimer's disease in people under the age of 65. Amyotrophic lateral sclerosis is also devastating; it is characterized by motor neuron degeneration that eventually causes respiratory failure with a median survival of three years after onset.
While different mutations of various genes have been linked to different phenotypes of FTD in the past, C9orf72 specifically has been linked to behavioral variant FTD. Certain pathology in FTD caused by the C9orf72 mutation can also include:
C9ORF72 is specifically linked to familial ALS, which affects about 10% of ALS patients. Traditionally, familial and sporadic cases of ALS have been clinically indistinguishable, which has made diagnosis difficult. The identification of this gene will therefore help in the future diagnosis of familial ALS. Slow diagnosis is also common for FTD, which can often take up to a year with many patients initially misdiagnosed with another condition. Testing for a specific gene that is known to cause the diseases would help with faster diagnoses. Possibly most importantly, the identification of this hexanucleotide repeat expansion is an extremely promising avenue for possible future therapies of both familial FTD and familial ALS, once the mechanism and function of the C9ORF72 protein is better comprehended. Furthermore, present research is being done to see if there is a correlation between C9ORF72 and other neurological diseases, such as motor neuron disease and Huntington's disease.
It is possible that genetic anticipation may exist for this mutation. However, only 1 in 4 families exhibited significant anticipation in this study (n=63)  It has been proposed that the amount of the repeat expansion increases with each successive generation, possibly causing the disease to be more severe in the next generation, showing onset up to a decade earlier with each successive generation after the carrier. The buildup of a repeat expansion with each generation is typically thought to occur because the DNA is unstable and therefore accumulates exponentially every time the gene is copied. No genetic evidence for this has yet been demonstrated for this mutation. There is also a demographic factor that should be considered in genetic predisposition, as some cohorts have found that there might be a founder effect for the C9orf72 mutation, which might have led to higher frequencies of the mutation in specific populations than others. Specifically this founder has been linked to Northern Europeans populations, namely Finland.
Since this mutation has been found to be the most common mutation identified in familial FTD and/or ALS, it is considered one of if not the most dependable candidates for genetic testing. Patients are considered eligible if the mother or father has had FTD and/or another family member has had ALS. There are also population and location risk factors in determining eligibility. Some studies have found that the mutation has a higher frequency in certain cohorts. Athena Diagnostics (Quest Diagnostics) announced in Spring 2012 the first clinically available testing service for detecting the hexanucleotide repeat expansion in the C9orf72 gene. Genetic counseling is recommended for the patients before a genetic test is ordered.
Likely function of C9ORF72 proteinEdit
C9ORF72 is predicted to be a full-length homologue of DENN proteins (where DENN stands for "differentially expressed in normal and neoplastic cells"). These proteins have a conserved DENN module consisting of an N-terminal longin domain, followed by the central DENN and C-terminal alpha-helical d-DENN domains. This led to DENNL72 being suggested as a new name for C9orf72.
Given the molecular role of known DENN modules, the C9ORF72-like proteins were predicted to function as Guanine nucleotide exchange factors (GEF), which activate small GTPases, most likely a Rab. Studies have provided some evidence to confirm this: C9ORF72 was found to regulate endosomal trafficking and autophagy in neuronal cells and primary neurons. This suggested that certain aspects of the ALS and FTD disease pathology might result from haploinsufficiency of C9ORF72, leading to a defect in intracellular membrane traffic, which adds to neuronal damage from RNA-mediated and dipeptide toxicities by reducing function of microglia, the macrophage-like cells of the brain.
GTPase targets of a stable C9ORF72-SMCR8-WDR41 complex include the Rag GTPases that simulate mTORC1 and so regulate macro-autophagy. Also, C9ORF72 and SMCR8 regulate the function of lysosomes. Although the GTPase involved on lysosomes is not yet identified, it might feasibly be Rab7A, which along with Rab5A and Rab11A, is activated by C9ORF72-SMCR8-WDR41 functioning as a GEF.
As well as activating GTPases (GEF), the same C9ORF72-SMCR8-WDR41 complex is proposed to inactivate GTPases, i.e. as a GTPase activating protein (GAP). This activity is proposed for Rag GTPases, paralleling the Rag-GAP activity of the FLCN-FNIP complex, which it resembles. In addition, the complex is a GAP for Rab8a and Rab11a, with cryo-EM identifying an ariginine finger conserved between FLCN and SMCR8.
DNA damage responseEdit
Repeat sequence expansion mutations in C9orf72 that lead to neurodegeneration in ALS/FTD display dysfunction of the nucleolus and of R-loop formation. Such dysfunctions can lead to DNA damage. Motor neurons with C9orf72 mutations were found to activate the DNA damage response (DDR) as indicated by up-regulation of DDR markers. If the DDR is insufficient to repair these DNA damages, apoptosis of the motor neurons is the likely result.
Sequence analysis further suggests that the C9ORF72 protein emerged early in eukaryotic evolution, and whereas most eukaryotes usually possess a single copy of the gene encoding the C9ORF72 protein, the eukaryotes Entamoeba and Trichomonas vaginalis possess multiple copies, suggestive of independent lineage-specific expansions in these species. The family is lost in most fungi (except Rhizopus) and plants.
Implications for future therapiesEdit
Overall, the C9ORF72 mutation holds great promise for future therapies for familial FTD and/or ALS to be developed. Currently, there is focus on more research to be done on C9ORF72 to further understand the exact mechanisms involved in the cause of the diseases by this mutation. A clearer understanding of the exact pathogenic mechanism will aid in a more focused drug therapies. Possible drug targets currently include the repeat expansion itself as well as increasing levels of C9ORF72. Blocking the toxic gain of RNA foci to prevent RNA sequestration might be helpful as well as making up for the lack of C9ORF72. Either of these targets as well as a combination of them might be promising future targets in minimizing the effects of the C9ORF72 repeat expansion.
C9ORF72 has been shown to interact with:
- GRCh38: Ensembl release 89: ENSG00000147894 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000028300 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- C9orf72 chromosome 9 open reading frame 72 [Homo sapiens] - Gene - NCBI
- DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. (October 2011). "Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS". Neuron. 72 (2): 245–56. doi:10.1016/j.neuron.2011.09.011. PMC 3202986. PMID 21944778.
- Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. (October 2011). "A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD". Neuron. 72 (2): 257–68. doi:10.1016/j.neuron.2011.09.010. PMC 3200438. PMID 21944779.
- Babić Leko M, Župunski V, Kirincich J, Smilović D, Hortobágyi T, Hof PR, Šimić G (2019). "C9orf72 Hexanucleotide Repeat Expansion". Behavioural Neurology. 2019: 2909168. doi:10.1155/2019/2909168. PMC 6350563. PMID 30774737.
- Bigio EH (December 2011). "C9ORF72, the new gene on the block, causes C9FTD/ALS: new insights provided by neuropathology". Acta Neuropathologica. 122 (6): 653–5. doi:10.1007/s00401-011-0919-7. PMC 3262229. PMID 22101324.
- Fong JC, Karydas AM, Goldman JS (2012). "Genetic counseling for FTD/ALS caused by the C9ORF72 hexanucleotide expansion". Alzheimer's Research & Therapy. 4 (4): 27. doi:10.1186/alzrt130. PMC 3506941. PMID 22808918.
- Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, et al. (April 2012). "Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion". Journal of Neurology, Neurosurgery, and Psychiatry. 83 (4): 358–64. doi:10.1136/jnnp-2011-301883. PMC 3388906. PMID 22399793.
- Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, et al. (March 2013). "The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS". Science. 339 (6125): 1335–8. Bibcode:2013Sci...339.1335M. doi:10.1126/science.1232927. PMID 23393093. S2CID 32244381.
- Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. (February 2013). "Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS". Neuron. 77 (4): 639–46. doi:10.1016/j.neuron.2013.02.004. PMC 3593233. PMID 23415312.
- Balendra R, Isaacs AM (September 2018). "C9orf72-mediated ALS and FTD: multiple pathways to disease". Nature Reviews. Neurology. 14 (9): 544–558. doi:10.1038/s41582-018-0047-2. PMC 6417666. PMID 30120348.
- Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, et al. (September 2015). "GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport". Nature. 525 (7567): 129–33. Bibcode:2015Natur.525..129F. doi:10.1038/nature14974. PMC 4631399. PMID 26308899.
- Cruts M, Engelborghs S, van der Zee J, Van Broeckhoven C (1993). "C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 25577942.
- Ratnavalli E, Brayne C, Dawson K, Hodges JR (June 2002). "The prevalence of frontotemporal dementia". Neurology. 58 (11): 1615–21. doi:10.1212/WNL.58.11.1615. PMID 12058088. S2CID 45904851.
- Herdewyn S, Zhao H, Moisse M, Race V, Matthijs G, Reumers J, et al. (June 2012). "Whole-genome sequencing reveals a coding non-pathogenic variant tagging a non-coding pathogenic hexanucleotide repeat expansion in C9orf72 as cause of amyotrophic lateral sclerosis". Human Molecular Genetics. 21 (11): 2412–9. doi:10.1093/hmg/dds055. PMC 3349421. PMID 22343411.
- Friedland RP, Shah JJ, Farrer LA, Vardarajan B, Rebolledo-Mendez JD, Mok K, Hardy J (2012). "Behavioral variant frontotemporal lobar degeneration with amyotrophic lateral sclerosis with a chromosome 9p21 hexanucleotide repeat". Frontiers in Neurology. 3: 136. doi:10.3389/fneur.2012.00136. PMC 3463813. PMID 23060854.
- Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, et al. (March 2012). "Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72". Brain. 135 (Pt 3): 765–83. doi:10.1093/brain/aws004. PMC 3286335. PMID 22366793.
- Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, et al. (March 2012). "Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features". Brain. 135 (Pt 3): 736–50. doi:10.1093/brain/awr361. PMC 3286330. PMID 22366791.
- Otomo A, Pan L, Hadano S (2012). "Dysregulation of the autophagy-endolysosomal system in amyotrophic lateral sclerosis and related motor neuron diseases". Neurology Research International. 2012: 498428. doi:10.1155/2012/498428. PMC 3407648. PMID 22852081.
- Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, et al. (January 2014). "C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies". Neurology. 82 (4): 292–9. doi:10.1212/WNL.0000000000000061. PMC 3929197. PMID 24363131.
- Sieben A, Van Langenhove T, Engelborghs S, Martin JJ, Boon P, Cras P, et al. (September 2012). "The genetics and neuropathology of frontotemporal lobar degeneration". Acta Neuropathologica. 124 (3): 353–72. doi:10.1007/s00401-012-1029-x. PMC 3422616. PMID 22890575.
- New Testing for ALS Archived 26 June 2012 at the Wayback Machine (2012)
- Söding J, Biegert A, Lupas AN (July 2005). "The HHpred interactive server for protein homology detection and structure prediction". Nucleic Acids Research. 33 (Web Server issue): W244-8. doi:10.1093/nar/gki408. PMC 1160169. PMID 15980461.
- Zhang D, Iyer LM, He F, Aravind L (2012). "Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease". Frontiers in Genetics. 3: 283. doi:10.3389/fgene.2012.00283. PMC 3521125. PMID 23248642.
- Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ (February 2013). "The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs". Bioinformatics. 29 (4): 499–503. doi:10.1093/bioinformatics/bts725. PMC 3570213. PMID 23329412.
- Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ, Barr FA (October 2010). "Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors". The Journal of Cell Biology. 191 (2): 367–81. doi:10.1083/jcb.201008051. PMC 2958468. PMID 20937701.
- Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V, et al. (July 2014). "C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking". Human Molecular Genetics. 23 (13): 3579–95. doi:10.1093/hmg/ddu068. PMC 4049310. PMID 24549040.
- O'Rourke JG, Bogdanik L, Yáñez A, Lall D, Wolf AJ, Muhammad AK, et al. (March 2016). "C9orf72 is required for proper macrophage and microglial function in mice". Science. 351 (6279): 1324–9. Bibcode:2016Sci...351.1324O. doi:10.1126/science.aaf1064. PMC 5120541. PMID 26989253.
- Amick J, Tharkeshwar AK, Amaya C, Ferguson SM (September 2018). Barr FA (ed.). "WDR41 supports lysosomal response to changes in amino acid availability". Molecular Biology of the Cell. 29 (18): 2213–2227. doi:10.1091/mbc.E17-12-0703. PMC 6249801. PMID 29995611.
- Wang M, Wang H, Tao Z, Xia Q, Hao Z, Prehn JH, et al. (April 2020). "C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis". Aging Cell. 19 (4): e13126. doi:10.1111/acel.13126. PMC 7189992. PMID 32100453.
- Ji YJ, Ugolino J, Zhang T, Lu J, Kim D, Wang J (April 2020). Kao A (ed.). "C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases". PLOS Genetics. 16 (4): e1008738. doi:10.1371/journal.pgen.1008738. PMC 7188304. PMID 32282804.
- Iyer S, Subramanian V, Acharya KR (17 October 2018). "C9orf72, a protein associated with amyotrophic lateral sclerosis (ALS) is a guanine nucleotide exchange factor". PeerJ. 6: e5815. doi:10.7717/peerj.5815. PMC 6195791. PMID 30356970.
- Tang D, Sheng J, Xu L, Zhan X, Liu J, Jiang H, et al. (May 2020). "Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a". Proceedings of the National Academy of Sciences of the United States of America. 117 (18): 9876–9883. doi:10.1073/pnas.2002110117. PMC 7211967. PMID 32303654.
- Farg MA, Konopka A, Soo KY, Ito D, Atkin JD (August 2017). "The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis". Human Molecular Genetics. 26 (15): 2882–2896. doi:10.1093/hmg/ddx170. PMID 28481984.
- Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, et al. (March 2012). "Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics". Brain. 135 (Pt 3): 794–806. doi:10.1093/brain/aws001. PMC 3286334. PMID 22366795.
- "C9orf72 Interaction Summary". BioGRID.
- Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Heusler AR, Mistry NA, et al. (October 2013). "RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention". Neuron. 80 (2): 415–28. doi:10.1016/j.neuron.2013.10.015. PMC 4098943. PMID 24139042.
|Wikimedia Commons has media related to C9orf72.|