Screening for rare variants in the coding region of ALS-associated genes at 9p21.2 and 19p13.3
Abstract
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes progressive muscle weakness, eventually resulting in death because of respiratory failure. Genetic variants are thought to predispose to the disease. A recent, large, genome-wide association study identified 2 loci that increase susceptibility to ALS. These 2 loci on chromosomes 9 and 19 consist of 4 genes: UNC13a, IFNK, MOBKL2b, and C9ORF72. A hexanucleotide repeat expansion in the noncoding region of C9ORF72 was recently identified as the cause of chromosome 9-linked ALS-FTD (frontotemporal dementia). In this study, our aim was to determine whether the coding regions of these genes harbor rare, nonsynonymous variants that play a role in ALS pathogenesis. In DNA from 1019 sporadic ALS patients and 1103 control subjects of Dutch descent, we performed a mutation screening analysis in the coding region of these 4 genes by resequencing the exons. A total of 16 amino acid-changing rare variations were identified, 11 in UNC13a and 5 on chromosome 9. Some of these were unique to ALS, but were detected in a single patient. None of the genes showed significant enrichment of rare variants in the coding sequence. Rare variants in the coding region of UNC13a, IFNK, MOBKL2b, and C9ORF72 are unlikely to be a genetic cause of ALS.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
VCP mutations are responsible for approximately 1-2% of familial ALS cases.
“but are also responsible for ~1-2% of familial ALS cases [241–243].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [242]
Cites
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., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.011 · Cited by 4,936 · see citing works
A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.010 · Cited by 4,409 · see citing works
Haine, M. M.-L., & Meeùs, N. (1986) · Cited by 3,463 · see citing works
Kiernan, M. C., Vucic, S., Cheah, B. C., Turner, M. R., Eisen, A., Hardiman, O., Burrell, J. R., & Zoing, M. C. (2011) · The Lancet · doi:10.1016/s0140-6736(10)61156-7 · Cited by 2,603 · see citing works
Majounie, E., Renton, A. E., Mok, K., Dopper, E. G., Waite, A., Rollinson, S., Chiò, A., Restagno, G., Nicolaou, N., Simon-Sanchez, J., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70043-1 · Cited by 1,210 · see citing works
A Groupwise Association Test for Rare Mutations Using a Weighted Sum Statistic
Madsen, B. E., & Browning, S. R. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000384 · Cited by 1,113 · see citing works
Pooled Association Tests for Rare Variants in Exon-Resequencing Studies
Price, A. L., Kryukov, G. V., de Bakker, P. I. W., Purcell, S. M., Staples, J., Wei, L.-J., & Sunyaev, S. R. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.04.005 · Cited by 755 · see citing works
Statistical analysis strategies for association studies involving rare variants
Bansal, V., Libiger, O., Torkamani, A., & Schork, N. J. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2867 · Cited by 455 · see citing works
van Es, M. A., Veldink, J. H., Saris, C. G. J., Blauw, H. M., van Vught, P. W. J., Birve, A., Lemmens, R., Schelhaas, H. J., Groen, E. J. N., Huisman, M. H. B., et al. (2009) · Nature Genetics · doi:10.1038/ng.442 · Cited by 398 · see citing works
Self-citationGenetics of motor neuron disorders: new insights into pathogenic mechanisms
Dion, P. A., Daoud, H., & Rouleau, G. A. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2680 · Cited by 313 · see citing works
Taylor, K. D., Norris, J. M., & Rotter, J. I. (2007) · Diabetes · doi:10.2337/db07-1324 · Cited by 307 · see citing works
Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study
Laaksovirta, H., Peuralinna, T., Schymick, J. C., Scholz, S. W., Lai, S.-L., Myllykangas, L., Sulkava, R. O., Jansson, L., Hernandez, D. G., Gibbs, J. R., et al. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70184-8 · Cited by 260 · see citing works
Shatunov, A., Mok, K. Y., Newhouse, S., Weale, M. E., Smith, B. N., Vance, C. A., Johnson, L., Veldink, J. H., van Es, M. A., van den Berg, L. H., et al. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70197-6 · Cited by 231 · see citing works
Self-citationGenetics of amyotrophic lateral sclerosis
Siddique, T., & Deng, H. (1996) · Human Molecular Genetics · doi:10.1093/hmg/5.supplement_1.1465 · Cited by 207 · see citing works
UNC13A is a modifier of survival in amyotrophic lateral sclerosis
Diekstra, F. P., van Vught, P. W. J., van Rheenen, W., Koppers, M., Pasterkamp, R. J., van Es, M. A., Schelhaas, H. J., de Visser, M., Robberecht, W., Damme, P. V., et al. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.10.029 · Cited by 144 · see citing works
Self-citationvan Es, M. A., Dahlberg, C., Birve, A., Veldink, J. H., van den Berg, L. H., & Andersen, P. M. (2009) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2009.181453 · Cited by 76 · see citing works
Self-citationvan Boxtel, R., Toonen, P. W., Verheul, M., van Roekel, H. S., Nijman, I. J., Guryev, V., & Cuppen, E. P. J. G. (2008) · BMC Genomics · doi:10.1186/1471-2164-9-460 · Cited by 30 · see citing works
Breakwell, S. (2011) · doi:10.1002/9781118785744.ch43 · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
- Authors
- Koppers, M., Groen, E. J. N., van Vught, P. W. J., van Rheenen, W., Witteveen, E., van Es, M. A., Pasterkamp, R. J., van den Berg, L. H., & Veldink, J. H.
- Affiliations
- University Medical Center Utrecht (NL)
- Corresponding author
- Veldink, Jan H.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 34
- Issue
- 5
- Pages
- 1518.e5-1518.e7
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2050790137
- Cited by
- 20
- References
- 18
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 2 · 2013: 3
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Prinses Beatrix Fonds
- VSB fonds
- (Kersten Foundation)
- The Netherlands ALS Foundation
- the van Meer Foundation
- Adessium Foundation
- Thierry Latran Foundation
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, rare variants, non-synonymous mutations, 19p13.3, UNC13A, C9orf72, hexanucleotide repeat expansion, ALS-FTD, genetic susceptibility, sporadic ALS, mutation detection, exome resequencing
- MeSH terms
- Amyotrophic Lateral Sclerosis, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 9, Female, Genetic Markers, Genetic Testing, Humans, Male, Netherlands, Risk Factors, Genetic Variation, Prevalence, Genetic Predisposition to Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
