Large C9orf72 Hexanucleotide Repeat Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are More Frequent Than Expected in the UK Population
Open accessAbstract
Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.
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C9orf72 expansion mutations are associated with ALS/FTLD and also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome.
“For instance, C9orf72 expansion mutations are associated not only with ALS/FTLD, but also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome, reinforcing the imperfect connection between clinical and molecular phenotypes and emphasizing the need for molecular diagnostics [155–164].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [156]
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- Authors
- Beck, J., Poulter, M., Hensman, D., Rohrer, J. D., Mahoney, C. J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., Orrell, R. W., Malaspina, A., Rowe, J., Brown, J., Hodges, J., Sidle, K., Polke, J. M., Houlden, H., Schott, J. M., Fox, N. C., Rossor, M. N., Tabrizi, S. J., Isaacs, A. M., Hardy, J., Warren, J. D., Collinge, J., & Mead, S.
- Affiliations
- MRC Prion Unit (GB)
- UCL Queen Square Institute of Neurology (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Queen Mary University of London (GB)
- University of Cambridge (GB)
- Corresponding author
- Mead, Simon
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 92
- Issue
- 3
- Pages
- 345-353
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3591848
- OpenAlex
- W2026340703
- Cited by
- 345
- References
- 25
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 24 · 2023: 24 · 2022: 31 · 2021: 21 · 2020: 20 · 2019: 21 · 2018: 27 · 2017: 21 · 2016: 24 · 2015: 44 · 2014: 41 · 2013: 35
- FWCI
- 30.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (068545/Z/02), 088324, 091673/Z/10/Z, 068545)
- National Institute for Health and Care Research (NF-SI-0512-10033, ACF-2009-18-016, NF-SI-0508-10123)
- Motor Neurone Disease Association (Orrell/Apr11/6075)
- Medical Research Council (MR/J004758/1, MR/J003832/1)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72, hexanucleotide repeat expansion, repeat-primed PCR, Southern blot, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, Alzheimer's disease, Creutzfeldt-Jakob disease, repeat instability, haplotypes, age of onset, 1958 British birth cohort
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Brain, DNA, United Kingdom, Haplotypes, Humans, Nerve Degeneration, Proteins, Cohort Studies, Microsatellite Repeats, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, DNA Repeat Expansion, Frontotemporal Lobar Degeneration
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