The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy
Open accessAbstract
Objective: Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3 , also contribute to cases of focal epilepsy. Methods: We used targeted capture and next‐generation sequencing to analyze 404 unrelated probands with focal epilepsy. We performed exome sequencing on two families with multiple members affected with focal epilepsy and linkage analysis on one of these. Results: In our cohort of 404 unrelated focal epilepsy patients, we identified five mutations in NPRL2 and five in NPRL3 . Exome sequencing analysis of two families with focal epilepsy identified NPRL2 and NPRL3 as the top candidate‐causative genes. Some patients had focal epilepsy associated with brain malformations. We also identified 18 new mutations in DEPDC5 . Interpretation: We have identified NPRL2 and NPRL3 as two new focal epilepsy genes that also play a role in the mTOR‐signaling pathway. Our findings show that mutations in GATOR1 complex genes are the most significant cause of familial focal epilepsy identified to date, including cases with brain malformations. It is possible that deregulation of cellular growth control plays a more important role in epilepsy than is currently recognized. ANN NEUROL 2016;79:120–131
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The text we found for this paper looks like another document, so the self-check wasn’t run.
Citations
Cites
The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607
Cutadapt removes adapter sequences from high-throughput sequencing reads
Martin, M. (2011) · EMBnet.journal · doi:10.14806/ej.17.1.200 · Cited by 33,889
BEDTools: a flexible suite of utilities for comparing genomic features
Quinlan, A. R., & Hall, I. M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq033 · Cited by 27,437
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194
Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012) · Fly · doi:10.4161/fly.19695 · Cited by 11,816
Van der Auwera, G. A., Carneiro, M. O., Hartl, C., Poplin, R., del Angel, G., Levy‐Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. (2013) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1110s43 · Cited by 6,687
Kumar, P., Henikoff, S., & Ng, P. C. (2009) · Nature Protocols · doi:10.1038/nprot.2009.86 · Cited by 6,521
Berg, A. T., Berkovic, S. F., Brodie, M. J., Buchhalter, J., Cross, J. H., Van Emde Boas, W., Engel, J., French, J., Glauser, T. A., Mathern, G. W., et al. (2010) · Epilepsia · doi:10.1111/j.1528-1167.2010.02522.x · Cited by 4,363
Self-citationMerlin—rapid analysis of dense genetic maps using sparse gene flow trees
Abecasis, G. R., Cherny, S. S., Cookson, W., & Cardon, L. R. (2001) · Nature Genetics · doi:10.1038/ng786 · Cited by 3,323
Cited by
Sorted by citations
mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
Thijs, R. D., Surges, R., O'Brien, T. J., & Sander, J. W. A. S. (2019) · The Lancet · doi:10.1016/s0140-6736(18)32596-0 · Cited by 2,359
Devinsky, O., Vezzani, A., O'Brien, T. J., Jetté, N., Scheffer, I. E., de Curtis, M., & Perucca, P. (2018) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2018.24 · Cited by 998
Self-citationSudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention
Devinsky, O., Hesdorffer, D. C., Thurman, D. J., Lhatoo, S. D., & Richerson, G. B. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)30158-2 · Cited by 743
The mTOR signalling cascade: paving new roads to cure neurological disease
Crino, P. B. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.81 · Cited by 368
Metadata
- Authors
- Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., Baldassari, S., Palombo, F., Epilepsy Electroclinical Study Group, Santucci, M., Meletti, S., Berkovic, S. F., Rubboli, G., Thomas, P. Q., Scheffer, I. E., Tinuper, P., Geoghegan, J., Schreiber, A. W., & Dibbens, L. M.
- Affiliations
- University of South Australia (AU)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Novocraft Technologies Sdn Bhd Selangor Malaysia
- Istituto delle Scienze Neurologiche di Bologna (IT)
- The University of Adelaide (AU)
- University of Modena and Reggio Emilia (IT)
- The University of Melbourne (AU)
- University of Copenhagen (DK)
- Royal Children's Hospital (AU)
- South Australia Pathology (AU)
- Corresponding author
- Dibbens, Leanne M.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2015-12-12
- Volume
- 79
- Issue
- 1
- Pages
- 120-131
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2302804942
- Cited by
- 246
- References
- 50
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 21 · 2023: 25 · 2022: 24 · 2021: 23 · 2020: 41 · 2019: 19 · 2018: 23 · 2017: 20 · 2016: 13
- FWCI
- 15.14
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- Australian Cancer Research Foundation
- National Health and Medical Research Council
- National Medical Research Council
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- focal epilepsy, NPRL2, NPRL3, mTOR signaling, GATOR1 complex, genetic epilepsy, brain malformations, familial epilepsy
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Epilepsies, Partial, Humans, Mutation, Pedigree, Repressor Proteins, Signal Transduction, Sequence Analysis, DNA, GTPase-Activating Proteins, Gene Expression Profiling, Tumor Suppressor Proteins, Multiprotein Complexes, TOR Serine-Threonine Kinases, Exome
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
