C9orf72

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Chromosome 9 open reading frame 72
Identifiers
Symbols C9orf72 ; ALSFTD; FTDALS
External IDs OMIM614260 HomoloGene10137 GeneCards: C9orf72 Gene
Orthologs
Species Human Mouse
Entrez 203228 73205
Ensembl ENSG00000147894 ENSMUSG00000028300
UniProt Q96LT7 n/a
RefSeq (mRNA) NM_001256054 NM_001081343
RefSeq (protein) NP_001242983 NP_001074812
Location (UCSC) Chr 9:
27.55 – 27.57 Mb
Chr 4:
35.19 – 35.23 Mb
PubMed search [1] [2]

C9orf72 (chromosome 9 open reading frame 72) is a protein which in humans is encoded by the gene C9orf72.

The human C9orf72 gene is located on the short (p) arm of chromosome 9 open reading frame 72, from base pair 27,546,542 to base pair 27,573,863. Its cytogenetic location is at 9p21.2.[1]

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.[2][3] 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). As of 2012, it is the most common mutation identified that is associated with familial FTD and/or ALS.

Gene location[edit]

Cytogenetic Location: 9p21.2

Molecular Location on chromosome 9: base pairs 27,546,542 to 27,573,863

The C9orf72 gene is located on the short (p) arm of chromosome 9 at position 21.2.

More precisely, the C9orf72 gene is located from base pair 27,546,542 to base pair 27,573,863 on chromosome 9.[4]

Mutation[edit]

The mutation of C9ORF72 is a hexanucleotide repeat expansion of the six letter string of nucleotides GGGGCC.[5] In a normal person, there are up to 30 repeats of this hexanucleotide, but in people with the mutation, the repeat can occur in the order of hundreds.[6] It is known that the mutation interferes with normal expression of the protein made by C9orf72, however the function of that protein is unknown (though see section below). 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. This drives the formation and accumulation of dipeptide repeat proteins corresponding multiple ribosomal reading frames on the mutation. This phenomenon was reported in a study led by Leonard Petrucelli, Dennis Dickson, Kevin Boylan, and Rosa Rademakers at Mayo Clinic in early 2013. [7]

Clinical significance[edit]

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.[8] 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.[9] 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.[10] Certain pathology in FTD caused by the C9orf72 mutation can also include:

  • TDP 43 in all C9 carriers[11]
  • Ubiquitin-binding protein 62[12]

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.[9] 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 hexanucelotide 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.[13][14]

Gene heritability[edit]

It has been found that paternal genetic anticipation exists for the mutation.[11] It has also been proposed that the amount of the repeat expansion increases with each successive generation, 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. 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.[10]

Gene testing[edit]

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.[9] 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.[15] Athena Diagnostics (Quest Diagnostics) announced in Spring 2012 the first clinically available testing service for detecting the hexanucleotide repeat expansion in the C9orf72 gene.[16] Genetic counseling is recommended for the patients before a genetic test is ordered.

Likely function[edit]

Using sensitive sequence analysis tools, such as PSI-BLAST and HHpred,[17] two groups have shown that C9ORF72 is a full-length homologue of DENN proteins (where DENN stands for “differentially expressed in normal and neoplastic cells”).[18][19] 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.[18] This has led to DENNL72 being suggested as a new name for C9orf72.[19]

Given the molecular role of known DENN modules,[20] the C9ORF72-like proteins are predicted to function as Guanine nucleotide exchange factors for small GTPases, most likely a Rab. A recent study provided the first experimental evidence to confirm this: C9ORF72 was found to regulate endosomal trafficking and autophagy in neuronal cells and primary neurons.[18][21] This suggests that certain aspects of the ALS and FTD disease pathology might result from haploinsufficiency of C9ORF72/DENNL72, leading to a defect in intracellular membrane traffic, either exocytosis or endocytosis, in addition to the strong possibility of RNA-mediated toxicity.

Evolutionary history[edit]

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. Interestingly, the family is lost in most fungi (except Rhizopus) and plants.[18][19]

Implications for future therapies[edit]

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.[22]

Interactions[edit]

C9ORF72 has been shown to interact with:

References[edit]

  1. ^ C9orf72 chromosome 9 open reading frame 72 [Homo sapiens] - Gene - NCBI
  2. ^ DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, et al. (2011). "Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS". Neuron 72 (2): 245–256. doi:10.1016/j.neuron.2011.09.011. PMC 3202986. PMID 21944778. 
  3. ^ Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, et al. (2011). "A Hexanucleotide Repeat Expansion in C9ORF72 is the Cause of Chromosome 9p21-Linked ALS-FTD". Neuron 72 (2): 257–268. doi:10.1016/j.neuron.2011.09.010. PMC 3200438. PMID 21944779. 
  4. ^ "C9orf72". Retrieved July 2013. 
  5. ^ Bigio EH (2011). "C9ORF72, the new gene on the block, causes C9FTD/ALS: New insights provided by neuropathology". Acta Neuropathologica 122 (6): 653–655. doi:10.1007/s00401-011-0919-7. PMC 3262229. PMID 22101324. 
  6. ^ Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, Karydas AM, Wu T, Ketelle RS, Baker MC, Hernandez MD, Coppola G, Geschwind DH, Rademakers R, Lee SE, Rosen HJ, Rabinovici GD, Seeley WW, Rankin KP, Boxer AL, Miller BL (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. 
  7. ^ Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW, Rademakers R, Boylan KB, Dickson DW, Petrucelli L (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. 
  8. ^ Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002). "The prevalence of frontotemporal dementia". Neurology 58 (11): 1615–1621. doi:10.1212/WNL.58.11.1615. PMID 12058088. 
  9. ^ a b c Herdewyn S, Zhao H, Moisse M, Race V, Matthijs G, Reumers J, Kusters B, Schelhaas HJ, van den Berg LH, Goris A, Robberecht W, Lambrechts D, Van Damme P (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): 2412–2419. doi:10.1093/hmg/dds055. PMC 3349421. PMID 22343411. 
  10. ^ a b 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. 
  11. ^ a b Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, Rush BK, Machulda MM, Fields JA, Ferman TJ, Baker M, Rutherford NJ, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J, Kantarci K, Jack CR, Parisi JE, Lucas JA, Petersen RC, Rademakers R (2012). "Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72". Brain : a Journal of Neurology 135 (Pt 3): 765–83. doi:10.1093/brain/aws004. PMC 3286335. PMID 22366793. 
  12. ^ Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, Yeatman T, Warrington EK, Schott JM, Fox NC, Rossor MN, Hardy J, Collinge J, Revesz T, Mead S, Warren JD (2012). "Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features". Brain : a Journal of Neurology 135 (Pt 3): 736–50. doi:10.1093/brain/awr361. PMC 3286330. PMID 22366791. 
  13. ^ 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. 
  14. ^ Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, Adamson G, Mudanohwo E, McColgan P, Haworth A, Wild EJ, Sweeney MG, Houlden H, Mead S, Tabrizi SJ (2014). "C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies". Neurology 82 (4): 292–9. doi:10.1212/WNL.0000000000000061. PMID 24363131. 
  15. ^ Sieben A, Van Langenhove T, Engelborghs S, Martin JJ, Boon P, Cras P, De Deyn PP, Santens P, Van Broeckhoven C, Cruts M (2012). "The genetics and neuropathology of frontotemporal lobar degeneration". Acta Neuropathologica 124 (3): 353–372. doi:10.1007/s00401-012-1029-x. PMC 3422616. PMID 22890575. 
  16. ^ New Testing for ALS (2012)
  17. ^ Söding J, Biegert A, Lupas AN (2005). "The HHpred interactive server for protein homology detection and structure prediction". Nucleic Acids Research 33 (Web Server issue): W244–W248. doi:10.1093/nar/gki408. PMC 1160169. PMID 15980461. 
  18. ^ a b c d 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. 
  19. ^ a b c Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ (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. 
  20. ^ Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ, Barr FA (2010). "Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors". The Journal of Cell Biology 191 (2): 367–381. doi:10.1083/jcb.201008051. PMC 2958468. PMID 20937701. 
  21. ^ Farg et al Human Molecular Genetics "C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking" Epub ahead of print, 27th February 2014 doi:10.1093/hmg/ddu068
  22. ^ Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, Rutherford NJ, Baker M, Knopman DS, Wszolek ZK, Parisi JE, Dickson DW, Petersen RC, Rademakers R, Jack CR, Josephs KA (2012). "Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics". Brain: a Journal of Neurology 135 (Pt 3): 794–806. doi:10.1093/brain/aws001. PMC 3286334. PMID 22366795. 
  23. ^ a b "C9orf72 Interaction Summary". BioGRID. 
  24. ^ Donnelly CJ, Zhang PW, Pham JT, Heusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis N, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD (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. PMID 24139042.