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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]
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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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A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
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InfluentialMutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
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Self-citationProtein aggregation in amyotrophic lateral sclerosis
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“This is supported by the finding that C9ORF72 protein levels are reduced in patients with increased repeat lengths [44, 68, 144, 193].”
BackgroundMicroglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
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“Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders.”
Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia
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“Hexanucleotide GGGGCC repeat expansions in a noncoding region of the C9ORF72 gene are the most common inherited cause of ALS and FTD (DeJesus-Hernandez et al., 2011; Renton et al., 2011).”
InfluentialThe role of mitochondria in amyotrophic lateral sclerosis
Smith, E. F., Shaw, P. J., & Vos, K. J. D. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.06.052 · Cited by 579
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Self-citationC9orf72 is required for proper macrophage and microglial function in mice
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“Microglial dysfunction is strongly tied to ALS/FTD pathogenesis (6), with mutations in progranulin causing FTD (7, 8) and variants in the microglial expressed genes TREM2 and TBK1 implicated in ALS (9–11).”
The epidemiology of frontotemporal dementia
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“2, found by association studies of familial FTDMND, followed by mutation analysis of positional candidate genes (DeJesus-Hernandez et al., 2011; Renton et al., 2011).”
Controversies and priorities in amyotrophic lateral sclerosis
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Tandem repeats mediating genetic plasticity in health and disease
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“Moreover, it has been suggested that the C9ORF72 expansion has a direct effect on the transcriptome, possibly via the formation of RNA foci [1,8]; if this is the case then transcriptome changes may represent a relatively upstream component of pathogenesis and a suitable therapeutic target.”
BackgroundPhosphorylated Tau in Alzheimer’s Disease and Other Tauopathies
Rawat, P., Sehar, U., Bisht, J., Selman, A., Culberson, J., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112841 · Cited by 509
“Studies indicate that TAR DNA binding protein-43, protein aggregates, and hexanucleotide repeat expansion in C9orf72 are the main causes detected in ALS patients [141].”
BackgroundThe nucleolus functions as a phase-separated protein quality control compartment
Frottin, F., Schueder, F., Tiwary, S., Gupta, R., Körner, R., Schlichthaerle, T., Cox, J., Jungmann, R., Hartl, F. U., & Hipp, M. S. (2019) · Science · doi:10.1126/science.aaw9157 · Cited by 500
Targeting nuclear RNA for in vivo correction of myotonic dystrophy
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Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics
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Biological metals and metal-targeting compounds in major neurodegenerative diseases
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“Several mechanistic hypotheses are emerging, including the loss of the C9ORF72 encoded protein, RNA-mediated toxicity (DeJesus-Hernandez et al., 2011; Renton et al., 2011), and toxic dipeptides from repeat-associated non-ATG (RAN) translation (Mori et al.”
BackgroundMethodInfluentialMori, K., Arzberger, T., Grässer, F. A., Gijselinck, I., May, S., Rentzsch, K., Weng, S., Schludi, M. H., van der Zee, J., Cruts, M., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1189-3 · Cited by 482
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SIRT1 in Neurodevelopment and Brain Senescence
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“…a functionally diverse set of genes have been identified including SOD1 (Rosen et al., 1993), TDP43 (Arai et al., 2006; Neumann et al., 2006), FUS (Kwiatkowski et al., 2009), VCP (Johnson et al., 2010), UBQLN2 (Deng et al., 2011), and C9ORF72 (DeJesus-Hernandez et al., 2011; Renton et al., 2011).”
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“We identified the same missense p.Ser59Leu mutation in one of these FTD-ALS families.”
BackgroundInfluentialModulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS
Butovsky, O., Siddiqui, S., Gabriely, G., Lanser, A. J., Dake, B., Murugaiyan, G., Doykan, C. E., Wu, P. M., Gali, R. R., Iyer, L. K., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62636 · Cited by 481
“It is now known that there are other forms of familial ALS-related mutations such as TDP-43 , FUS , and the newly discovered mutation in a noncoding region of C9ORF72 (79, 80) , which is the most common known genetic cause of fALS (46”
Converging pathways in neurodegeneration, from genetics to mechanisms
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CGG Repeat-Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome
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“RAN translation was recently shown to occur through the C9orf72 GGGGCC repeat expansion that causes ALS and frontotemporal dementia (Ash et al., 2013; DeJesus-Hernandez et al., 2011; Mori et al., 2013; Renton et al., 2011).”
Efficient CRISPR/Cas9 genome editing with low off-target effects in zebrafish
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“…the first intron of the C9orf72, the human ortholog of C13H9orf72, has recently been shown to be causative for most cases of familial frontotemporal lobar D ev el op m en t degeneration and amyotrophic lateral sclerosis (DeJesus-Hernandez et al., 2011; Renton et al., 2011; Gijselinck et al., 2012).”
Background30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?
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Alzheimer’s Disease Genetics: From the Bench to the Clinic
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Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1
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“, 2008) and C9orf72 (DeJesus-Hernandez et al., 2011; Renton et al., 2011) have not yet translated into the creation of animal models that are as widely accepted as SOD1 transgenic mice (Sreedharan and Brown, 2013).”
BackgroundInfluentialRisk factors for amyotrophic lateral sclerosis
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Pre-mRNA splicing in disease and therapeutics
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Detection of long repeat expansions from PCR-free whole-genome sequence data
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Self-citationMahoney, C., Beck, J. A., Rohrer, J. D., Lashley, T., Mok, K. Y., Shakespeare, T. J., Yeatman, T., Warrington, E. K., Schott, J. M., Fox, N. C., et al. (2012) · Brain · doi:10.1093/brain/awr361 · Cited by 452
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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