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Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS
Open accessAbstract
Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
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“The GGGGCC repeat expansion suppresses the production of C9ORF72 protein by inhibiting transcription (140, 153, 225, 369, 497, 520).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [140]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Approximately 10% of ALS cases are familial with autosomal dominant inheritance of mutations reported in at least 15 genes, including to name a few SOD1 , TARDBP , FUS , ANG , and OPTN (11, 18, 174, 465), and an expanded hexanucleotide repeat of GGGGCC in a noncoding region of the C9ORF72 gene (140, 497).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [140]
In the citing paper
“They can also cross the BBB by upregulating the expression of tight junction proteins in the BBB with the assistance of endothelial cell monocarboxylate transport proteins (56).”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [56]
In the citing paper
“The most common genes identified in clinical practice include SOD1, C9ORF72, TARDBP, FUS, and OPTNTD-P43 (55–57, 73, 74).”
From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [56]
In the citing paper
“In 2011, the seminal discovery of disease-associated expansion mutations within the C9orf72 gene uncovered the most common genetic cause of inherited ALS and FTD, accounting for 23–47% of familial cases and 4–21% of sporadic disease.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [141]
In the citing paper
“Unaffected individuals carry 2–30 repeated stretches of GGGGCC within the first intron of the gene, but patients with C9orf72-associated ALS-FTD harbor several hundred to thousands of repeats [141,142].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [141]
In the citing paper
“Mutation in C9orf72 accounts for 40% of familial ALS and FTD cases.303,304”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [304]
In the citing paper
“C9orf72 intronic hexanucleotide repeat expansion (GGGGCC) was identified as the most common genetic cause of FTD and ALS.304,335”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [304]
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Relationships between Stress Granules, Oxidative Stress, and Neurodegenerative Diseases
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BackgroundInfluentialThe gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS)
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Pathogenesis of FUS-associated ALS and FTD: insights from rodent models
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“The most frequent genetic mutation linking ALS and FTD is a hexanucleotide (G4C2) repeat expansion within an intronic promoter region of the C9ORF72 gene [20, 66], accounting for around 35 % fALS cases [65] and around 25 % FTD cases [85].”
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BackgroundInfluentialIntercellular Spread of Protein Aggregates in Neurodegenerative Disease
Davis, A. A., Leyns, C. E. G., & Holtzman, D. M. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100617-062636 · Cited by 131
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BackgroundInfluentialXiao, S., MacNair, L., McGoldrick, P., McKeever, P. M., McLean, J. R., Zhang, M., Keith, J. L., Zinman, L. H., Rogaeva, E. A., & Robertson, J. (2015) · Annals of Neurology · doi:10.1002/ana.24469 · Cited by 154
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“Microsatellite repeat expansion disorders, such as myotonic dystrophy (DM), fragile X-associated tremor/ataxia syndrome (FXTAS), C9orf72-linked amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD), spinocerebellar ataxia type 31 (SCA31), and other several types of SCA, are a group of neurological and neu…”
Human-specific tandem repeat expansion and differential gene expression during primate evolution
Sulovari, A., Li, R., Audano, P. A., Porubskỳ, D., Vollger, M. R., Logsdon, G. A., Warren, W. C., Pollen, A. A., Chaisson, M., Eichler, E. E., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1912175116 · Cited by 134
“This repeat, which has been shown to expand in up to half of familial ALS cases, causes the loss of one C9orf72 isoform while increasing repeat-containing RNA foci in the nucleus (57, 58).”
BackgroundDistinct partitioning of ALS associated TDP-43, FUS and SOD1 mutants into cellular inclusions
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“An expanded hexanucleotide repeat in the C9orf72 gene has been identified recently as the most common known genetic cause of both FTD and ALS [9, 20, 25].”
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“In addition, there is great interest in the recently discovered C9orf72 mutation (DeJesus-Hernandez et al., 2011; Renton et al., 2011).”
BackgroundFused in sarcoma (FUS): An oncogene goes awry in neurodegeneration
Dormann, D., & Haass, C. (2013) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2013.03.006 · Cited by 140
“Moreover, in 2011, abnormal expansion of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene was identified as a common genetic cause of both FTLD and ALS (Dejesus-Hernandez et al., 2011; Gijselinck et al., 2012; Renton et al., 2011).”
BackgroundLipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency
Evers, B. M., Rodríguez‐Navas, C., Tesla, R., Prange‐Kiel, J., Wasser, C. R., Yoo, K. S., McDonald, J. G., Cenik, B., Ravenscroft, T. A., Plattner, F., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.056 · Cited by 133
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The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients
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“Firstly, C9orf72 transcription can be decreased by up to 50 % in expansion carriers [11, 18].”
BackgroundInfluentialAdvances in CRISPR-Cas systems for RNA targeting, tracking and editing
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Mitochondrial dysfunction in amyotrophic lateral sclerosis – a valid pharmacological target?
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“More recently, hexanucleotide expansion in the C9ORF72 gene has been found to be a common genetic cause for ALS (Dejesus-Hernandez et al., 2011; Renton et al., 2011).”
BackgroundCDC7 inhibition blocks pathological TDP‐43 phosphorylation and neurodegeneration
Liachko, N. F., McMillan, P. J., Guthrie, C. R., Bird, T. D., Leverenz, J. B., & Kraemer, B. C. (2013) · Annals of Neurology · doi:10.1002/ana.23870 · Cited by 135
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C9orf72 arginine-rich dipeptide repeat proteins disrupt karyopherin-mediated nuclear import
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“A GGGGCC hexanucleotide repeat expansion (HRE) in C9orf72 is the most common known cause of amyotrophic lateral sclerosis (ALS) and is also a major cause of frontotemporal dementia (FTD) and the ALS/FTD overlap syndrome (DeJesus-Hernandez et al., 2011; Renton et al., 2011; Majounie et al., 2012).”
BackgroundFrontotemporal Lobar Degeneration: Epidemiology, Pathology, Diagnosis and Management
Seltman, R. E., & Matthews, B. R. (2012) · CNS Drugs · doi:10.2165/11640070-000000000-00000 · Cited by 132
“[93,136] This chromosome 9 GGGGCC expansion accounts for more familial cases of ALS than any of the other formerly identified genetic causes of familial ALS, including SOD1, TARDBP, FUS, VCP and OPTN[136] and more familial cases of FTD thanMAPT and PGRN.[103] 7.”
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“The most common genetic cause of ALS, with or without a frontotemporal dementia, is an abnormal expansion of a GGGGCC hexanucleotide repeat in C9orf72 [11, 48].”
BackgroundSelf-citationAdvances in motor neurone disease
Bäumer, D., Talbot, K., & Turner, M. R. (2014) · Journal of the Royal Society of Medicine · doi:10.1177/0141076813511451 · Cited by 134
“The single most frequent genetic cause is an intronic hexanucleotide repeat expansion in open reading frame 72 on chromosome 9 (C9orf72).(12) Mutations in SOD1, TARDBP and FUS occur in <10% of cases in population-based studies, and mutations in other genes are even more uncommon (Table 1).”
BackgroundA zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism
Swinnen, B., Bento‐Abreu, A., Gendron, T. F., Boeynaems, S., Bogaert, E., Nuyts, R., Timmers, M., Scheveneels, W., Hersmus, N., Wang, J., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-017-1796-5 · Cited by 137
The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
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Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy
Suzuki, N., Nishiyama, A., Warita, H., & Aoki, M. (2022) · Journal of Human Genetics · doi:10.1038/s10038-022-01055-8 · Cited by 148
“The ALS-causing mutations in C9ORF72 are hexanucleotide repeat expansion in intron 1 [20, 21].”
BackgroundMolecular and cellular mechanisms of selective vulnerability in neurodegenerative diseases
Kampmann, M. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00806-0 · Cited by 142
“Frontotemporal dementia (FTD) describes a diverse set of clinical symptoms linked to the underlying pathology of frontotemporal lobar degeneration.”
InfluentialThe roles of the nuclear pore complex in cellular dysfunction, aging and disease
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Self-citationCommon Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
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“Another, more specific example of how altered RNA homoeostasis, autophagy, and protein aggregation can be genetically linked by a single disease gene is the most frequently mutated gene in ALS/FTD patients: C9ORF72 [8,9].”
BackgroundInfluentialSchludi, M. H., Becker, L., Garrett, L., Gendron, T. F., Zhou, Q., Schreiber, F., Popper, B., Dimou, L., Strom, T. M., Winkelmann, J., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1711-0 · Cited by 137
“The repeat expansion inhibits C9orf72 expression, and sense and antisense transcripts may cause toxicity by sequestering RNA-binding proteins in nuclear foci [6, 28].”
BackgroundAntisense oligonucleotides in neurological disorders
Wurster, C. D., & Ludolph, A. C. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418776932 · Cited by 133
Dafinca, R., Barbagallo, P., Farrimond, L. E., Candalija, A., Scaber, J., Ababneh, N. A., Sathyaprakash, C., Vowles, J., Cowley, S. A., & Talbot, K. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.03.023 · Cited by 142
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Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis
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“Two other neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked to the expansion of the hexanucleotide repeat GGGGCC in the noncoding region of the C9ORF72 locus [57,58] that was found to give folded G4s [59].”
BackgroundRNA-driven phase transitions in biomolecular condensates
Wadsworth, G. M., Srinivasan, S., Lai, L. B., Datta, M., Gopalan, V., & Banerjee, P. R. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.09.005 · Cited by 136
SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease
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Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier
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Inside out: the role of nucleocytoplasmic transport in ALS and FTLD
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“Moreover, patients carrying hexanucleotide repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72), the most common genetic cause of ALS-FTLD [25, 100], have repeat RNA foci which sequester numerous RNA-binding proteins [20, 38, 64, 81].”
BackgroundRelationship between C9orf72 repeat size and clinical phenotype
Mossevelde, S. V., van der Zee, J., Cruts, M., & Broeckhoven, C. V. (2017) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2017.02.008 · Cited by 128
Bakthavachalu, B., Huelsmeier, J., Sudhakaran, I. P., Hillebrand, J., Singh, A., Petrauskas, A., Thiagarajan, D., Sankaranarayanan, M., Mizoue, L. S., Anderson, E. N., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.04.032 · Cited by 127
Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology
Nana, A. L., Sidhu, M., Gaus, S. E., Hwang, J., Li, L., Park, Y., Kim, E. J., Pasquini, L., Allen, I. E., Rankin, K. P., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1942-8 · Cited by 123
Self-citationMehta, A. R., Gregory, J. M., Dando, O., Carter, R. N., Burr, K., Nanda, J., Story, D., McDade, K., Smith, C., Morton, N. M., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-020-02252-5 · Cited by 122
The DNA Methylation in Neurological Diseases
Younesian, S., Yousefi, A., Momeny, M., Ghaffari, S. H., & Bashash, D. (2022) · Cells · doi:10.3390/cells11213439 · Cited by 141
“The presence of pathogenic hexanucleotide G4C2 repeats expansion (pHRE) in intron 1, between non-coding exons 1a and 1b of the gene C9orf72, leads to the development of C9-ALS/FTD by loss-of-function and/or toxic gain-of-function mechanisms.”
BackgroundInfluentialWhat causes neurodegenerative disease?
Armstrong, R. A. (2020) · Folia Neuropathologica · doi:10.5114/fn.2020.96707 · Cited by 143
Pathological stress granules in Alzheimer’s disease
Ash, P. E. A., Vanderweyde, T. E., Youmans, K. L., Apicco, D. J., & Wolozin, B. (2014) · Brain Research · doi:10.1016/j.brainres.2014.05.052 · Cited by 129
Splice Modulating Therapies for Human Disease
Spitali, P., & Aartsma-Rus, A. M. (2012) · Cell · doi:10.1016/j.cell.2012.02.014 · Cited by 130
Repeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress
Westergard, T., McAvoy, K., Russell, K. A., Wen, X., Pang, Y., Verdone, B. M., Pasinelli, P., Trotti, D., & Haeusler, A. R. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809423 · Cited by 126
“…features described for many other NRE-linked neurological and neuromuscular disorders, which include somatic NRE-linked genome instability (DeJesus-Hernandez et al, 2011; Renton et al, 2011); the bidirectional transcription of the NRE locus generating both sense, (G4C2)n, and antisense,…”
BackgroundThe Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis
Pradhan, J., Noakes, P. G., & Bellingham, M. C. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00368 · Cited by 133
“In addition to this, the Ca2+ buffering capacity of MNs in ALS is weakened at an early age, with impairment of the Ca2+ ATPase and Na+/Ca2+ exchanger adding to the cytoplasmic Ca2+ load (DeJesus-Hernandez et al., 2011; Sirabella et al., 2018).”
BackgroundRodent models of TDP-43: Recent advances
Tsao, W., Jeong, Y. H., Lin, S. Z., Ling, J. P., Price, D. L., Chiang, P., & Wong, P. C. (2012) · Brain Research · doi:10.1016/j.brainres.2012.04.031 · Cited by 129
Lattante, S., Ciura, S., Rouleau, G. A., & Kabashi, E. (2015) · Trends in Genetics · doi:10.1016/j.tig.2015.03.005 · Cited by 138
miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy
Karnati, H. K., Panigrahi, M. K., Gutti, R. K., Greig, N. H., & Tamargo, I. A. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150395 · Cited by 126
“Banks and colleagues have also demonstrated (cid:1) related protein-1 (LRP-1) antisense phosphorothioate oligodeoxynucleotides to cross the BBB, and Recent studies have shown that exosomes can as good delivery agents for miRNAs across the because they can protect miRNAs from RNAase [154–157].”
Genetic screening in sporadic ALS and FTD
Turner, M. R., Al‐Chalabi, A., Chiò, A., Hardiman, O. M., Kiernan, M. C., Rohrer, J. D., Rowe, J. B., Seeley, W. W., & Talbot, K. (2017) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-315995 · Cited by 125
Self-citationComprehensive analysis of the mutation spectrum in 301 German ALS families
Müller, K., Brenner, D., Weydt, P., Meyer, T., Grehl, T., Petri, S., Großkreutz, J., Schuster, J., Volk, A. E., Borck, G., et al. (2018) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-317611 · Cited by 131
Béland, L.-C., Markovinovic, A., Jakovac, H., De Marchi, F., Bilic, E., Mazzini, L., Kriz, J., & Munitic, I. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa124 · Cited by 125
The role of amyloid oligomers in neurodegenerative pathologies
Wells, C., Brennan, S. E., Keon, M., & Ooi, L. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.03.113 · Cited by 131
TDP ‐43 binds and transports G ‐quadruplex‐containing m RNA s into neurites for local translation
Ishiguro, A., Kimura, N., Watanabe, Y., Watanabe, S., & Ishihama, A. (2016) · Genes to Cells · doi:10.1111/gtc.12352 · Cited by 127
Troakes, C., Maekawa, S., Wijesekera, L., Rogelj, B., Siklós, L., Bell, C., Smith, B., Newhouse, S., Vance, C., Johnson, L., et al. (2012) · Neuropathology · doi:10.1111/j.1440-1789.2011.01286.x · Cited by 124
“To ascertain if patient DNA samples extracted from frontal cortex tissue harbored the GGGGCC hexanucleotide expansion in C9orf72, we performed the repeat primer PCR reaction as previously described.(17,18) Individual PCR reactions contained a final concentration of 7% dimethyl sulfoxide, 1 mol betaine, 0.”
BackgroundMethodProgressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice
Ghazi-Noori, S., Froud, K. E., Mizielinska, S., Powell, C., Smidak, M., Fernandez de Marco, M., O’Malley, C., Farmer, M., Parkinson, N., Fisher, E. M. C., et al. (2012) · Brain · doi:10.1093/brain/aws006 · Cited by 115
Lehmer, C., Oeckl, P., Weishaupt, J. H., Volk, A. E., Diehl‐Schmid, J., Schroeter, M. L., Lauer, M., Kornhuber, J., Levin, J., Fassbender, K., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201607486 · Cited by 118
“Formation of repeat RNA foci in the nucleus and the accompanying sequestration of RNA-binding proteins are thought to alter RNA processing (DeJesus-Hernandez et al, 2011).”
TMEM 106B p.T185S regulates TMEM 106B protein levels: implications for frontotemporal dementia
Nicholson, A. M., Finch, N. A., Wojtas, A., Baker, M. C., Perkerson, R. B., Castanedes‐Casey, M., Rousseau, L., Benussi, L., Binetti, G. G., Ghidoni, R., et al. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12329 · Cited by 124
Self-citationDifferential contribution of microglia and monocytes in neurodegenerative diseases
Baufeld, C., O'Loughlin, E. K., Calcagno, N., Madore, C., & Butovsky, O. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1795-7 · Cited by 128
Genetic Convergence Brings Clarity to the Enigmatic Red Line in ALS
Cook, C. N., & Petrucelli, L. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.032 · Cited by 126
Beckers, J., Tharkeshwar, A. K., & Damme, P. V. (2021) · Autophagy · doi:10.1080/15548627.2021.1872189 · Cited by 132
“have been proposed [10,37,38]: 1) Haploinsufficiency of the C9orf72 gene [38,39], 2) Sequestration of RNA-binding proteins (RNPs) by RNA foci containing the C9orf72 HRE RNA [34,38,40] and 3) Repeat-associated non-AUG (RAN) translation of the HRE resulting in dipeptide repeat proteins (DPRs) [40,41].”
BackgroundInfluentialvan Blitterswijk, M., Gendron, T. F., Baker, M., DeJesus‐Hernandez, M., Finch, N. A., Brown, P. H., Daughrity, L. M., Murray, M. E., Heckman, M. G., Jiang, J., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1480-6 · Cited by 127
Self-citationBenatar, M. G., & Wuu, J. (2012) · Neurology · doi:10.1212/wnl.0b013e31826e9b1d · Cited by 123
Phenotypic Heterogeneity of Monogenic Frontotemporal Dementia
Benussi, A., Padovani, A., & Borroni, B. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00171 · Cited by 129
“Two different protein isoforms of the C9orf72 gene are predicted to be generated from a total of three different transcripts variants, depending on the localization of the GGGGCC repeat, either in the promoter or in the intron 1 of the gene (DeJesus-Hernandez et al., 2011).”
BackgroundInfluentialGenetic counselling in ALS: facts, uncertainties and clinical suggestions
Chiò, A., Battistini, S., Calvo, A., Caponnetto, C., Conforti, F. L., Corbo, M., Giannini, F., Mandrioli, J., Mora, G., Sabatelli, M., et al. (2013) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2013-305546 · Cited by 123
Mutant C9orf72 human iPSC‐derived astrocytes cause non‐cell autonomous motor neuron pathophysiology
Zhao, C. N., Devlin, A., Chouhan, A. K., Selvaraj, B. T., Stavrou, M., Burr, K., Brivio, V., He, X., Mehta, A. R., Story, D., et al. (2019) · Glia · doi:10.1002/glia.23761 · Cited by 129
“The intronic hexanucleotide repeat expansion GGGGCC (G 4 C 2 ) in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common genetic cause of ALS, accounting for ~40% of fALS and ~10% of sALS (DeJesus-Hernandez et al., 2011; Renton et al., 2011).”
BackgroundCNS glucose metabolism in Amyotrophic Lateral Sclerosis: a therapeutic target?
Tefera, T. W., Steyn, F. J., Ngo, S. T., & Borges, K. (2021) · Cell & Bioscience · doi:10.1186/s13578-020-00511-2 · Cited by 122
“Distinct metabolic profiles were found in fibroblasts and reprogrammed induced astrocytes derived from C9ORF72 and sporadic patients with ALS when compared to control astrocytes.”
BackgroundInfluentialThe metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients
Cistaro, A., Pagani, M., Montuschi, A., Calvo, A., Moglia, C., Canosa, A., Restagno, G., Brunetti, M., Traynor, B. J., Nobili, F., et al. (2014) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-013-2667-5 · Cited by 129
“Recently, our group and others have demonstrated that a GGGG CC hexanucleotide repeat expansion in the C9ORF72 gene located on chromosome 9p21 is the commonest cause of familial ALS and also accounts for up to 10 % of apparently sporadic ALS [3–7].”
BackgroundDiagnosis and Management of Behavioral Variant Frontotemporal Dementia
Pressman, P., & Miller, B. L. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.11.006 · Cited by 127
“(46) TDP-43 TDP-43 protein is found in approximately one-half of bvFTD cases on histological examination, and is seen in all cases of FTD-ALS.”
BackgroundInfluentialSelf-citationRepetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients
Prudencio, M., Gonzales, P. K., Cook, C. N., Gendron, T. F., Daughrity, L. M., Song, Y., Ebbert, M. T. W., van Blitterswijk, M., Zhang, Y.-J., Jansen-West, K., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx233 · Cited by 122
Self-citationDevelopment of disease-modifying drugs for frontotemporal dementia spectrum disorders
Panza, F., Lozupone, M., Seripa, D., Daniele, A., Watling, M., Giannelli, G., & Imbimbo, B. P. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0330-x · Cited by 122
Favaro, F. P., Alvizi, L., Zechi‐Ceide, R. M., Bertola, D. R., Félix, T. M., Souza, J., Raskin, S., Twigg, S. R. F., Weiner, A. M. J., Armas, P., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.11.020 · Cited by 122
Ligand-induced native G-quadruplex stabilization impairs transcription initiationPreprint
Li, C., Wang, H., Yin, Z., Fang, P., Xiao, R., Xiang, Y., Wang, W., Li, Q., Huang, B., Huang, J., et al. (2021) · Genome Research · doi:10.1101/gr.275431.121 · Cited by 115
“…such as alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome, C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), and breast cancer (Law et al. 2010; DeJesus-Hernandez et al. 2011; Renton et al. 2011; Shioda et al. 2018; Hänsel-Hertsch et al. 2020).”
BackgroundDiekstra, F. P., Deerlin, V. M. V., Swieten, J. C. V., Al‐Chalabi, A., Ludolph, A. C., Weishaupt, J. H., Hardiman, O. M., Landers, J. E., Brown, R. H., van Es, M. A., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24198 · Cited by 121
Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease
Brás, J., Guerreiro, R. J., & Hardy, J. (2012) · Nature reviews. Neuroscience · doi:10.1038/nrn3271 · Cited by 124
Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP Kinase
Morfini, G. A., Bosco, D. A., Brown, H. E., Gatto, R. G., Kamińska, A., Song, Y., Molla, L., Baker, L. M., Marangoni, N., Berth, S. H., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065235 · Cited by 121
Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts
Kramer, N. J., Carlomagno, Y., Zhang, Y., Almeida, S., Cook, C. N., Gendron, T. F., Prudencio, M., van Blitterswijk, M., Belzil, V., Couthouis, J., et al. (2016) · Science · doi:10.1126/science.aaf7791 · Cited by 123
Self-citationLinking hnRNP Function to ALS and FTD Pathology
Purice, M. D., & Taylor, J. P. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00326 · Cited by 128
“Notably, each of its three RRMs has a distinct RNA-binding profile (Dember et al., 1996; Forch et al., 2002; Kim et al., 2007; Bauer et al., 2012; Wang et al., 2014).”
BackgroundFrontotemporal dementia: a bridge between dementia and neuromuscular disease
Ng, A. S. L., Rademakers, R., & Miller, B. L. (2014) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12638 · Cited by 127
Self-citationClinical and genetic heterogeneity of amyotrophic lateral sclerosis
Sabatelli, M., Conte, A., & Zollino, M. (2013) · Clinical Genetics · doi:10.1111/cge.12117 · Cited by 122
“However, reduced expression of one of the transcripts of C9ORF72 has been observed as well, consistent with a loss-of-function mechanism (36, 37).”
BackgroundNordin, A., Akimoto, C., Wuolikainen, A., Alstermark, H., Jonsson, P., Birve, A., Marklund, S. L., Graffmo, K. S., Forsberg, K., Brännström, T., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv064 · Cited by 120
Ebbert, M., Farrugia, S. L., Sens, J. P., Jansen‐West, K. R., Gendron, T. F., Prudencio, M., McLaughlin, I. J., Bowman, B. N., Seetin, M. G., DeJesus‐Hernandez, M., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0274-4 · Cited by 125
“Repeat plasmids To generate the G4C2 repeat 423 and 774 expression vectors, we used muscle or spleen DNA from an affected C9orf72 expansion carrier as a template in a nested PCR strategy.”
InfluentialSelf-citationWhitwell, J. L., Boeve, B. F., Weigand, S. D., Senjem, M. L., Gunter, J. L., Baker, M., DeJesus‐Hernandez, M., Knopman, D. S., Wszolek, Z. K., Petersen, R. C., et al. (2015) · European Journal of Neurology · doi:10.1111/ene.12675 · Cited by 125
“Genetic analyses were performed as previously described [1,2,4,13].”
BackgroundMethodSelf-citationGalimberti, D., Fenoglio, C., Serpente, M., Villa, C., Bonsi, R., Arighi, A., Fumagalli, G., Bo, R. D., Bruni, A. C., Anfossi, M., et al. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.01.031 · Cited by 119
Metadata
- Authors
- DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., Sengdy, P., Hsiung, G.-Y. R., Karydas, A., Seeley, W. W., Josephs, K. A., Coppola, G., Geschwind, D. H., Wszolek, Z. K., Feldman, H., Knopman, D. S., Petersen, R. C., Miller, B. L., Dickson, D. W., Boylan, K. B., Graff-Radford, N. R., & Rademakers, R.
- Affiliations
- University of British Columbia (CA)
- Mayo Clinic (US)
- University of California, San Francisco (US)
- Mayo Clinic in Florida (US)
- University of California, Los Angeles (US)
- Corresponding author
- Mackenzie, Ian R.
- Rademakers, Rosa
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 72
- Issue
- 2
- Pages
- 245-256
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3202986
- OpenAlex
- W2154945114
- Semantic Scholar
- a14363772a9926a299f67b9fdebfb404d9b6100d
- Cited by
- 4,936
- References
- 58
- Citations by year
- 2026: 192 · 2025: 241 · 2024: 298 · 2023: 327 · 2022: 348 · 2021: 407 · 2020: 383 · 2019: 338 · 2018: 342 · 2017: 338 · 2016: 324 · 2015: 354 · 2014: 330 · 2013: 349 · 2012: 310
- FWCI
- 209.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P50 AG016574)
- National Institute of Neurological Disorders and Stroke (NS057567, 1RC2NS070276, P50NS072187)
- Canadian Institutes of Health Research (74580, 179009)
- Dystonia Medical Research Foundation
- Amyotrophic Lateral Sclerosis Association
- Mayo Foundation for Medical Education and Research
- National Institutes of Health (R01 AG026251, R01 AG037491, R01 NS065782)
- Larry L. Hillblom Foundation (P50 AG1657303)
- Mayo Clinic (U01 AG006786)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- C9orf72, frontotemporal dementia, amyotrophic lateral sclerosis, chromosome 9p21, TDP-43 pathology, alternative splicing, familial neurodegenerative disease, genetic linkage
- MeSH terms
- C9orf72 Protein, Alleles, Amyotrophic Lateral Sclerosis, Chromosomes, Human, Pair 9, Female, Genotype, Haplotypes, Humans, Male, Pedigree, Proteins, Microsatellite Repeats, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, DNA Repeat Expansion, Frontotemporal Dementia
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