Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome.
Open accessAbstract
Disruption of cellular iron homeostasis can contribute to neurodegeneration. In mammals, two iron-regulatory proteins (IRPs) shape the expression of the iron metabolism proteome. Targeted deletion of Ireb2 in a mouse model causes profoundly disordered iron metabolism, leading to functional iron deficiency, anemia, erythropoietic protoporphyria, and a neurodegenerative movement disorder. Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2. This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder. Cellular phenotyping at the RNA and protein level was performed using patient and control lymphoblastoid cell lines, and established experimental assays. Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model. The patient's cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression. These results confirm that IRP2 is essential for regulation of iron metabolism in humans, and reveal a previously unrecognized subclass of neurodegenerative disease. Greater understanding of how the IRPs mediate cellular iron distribution may ultimately provide new insights into common and rare neurodegenerative processes, and could result in novel therapies.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Four diagnoses were initially reported as variants of uncertain significance but were upgraded with additional data, including publication of another novel gene, IREB2, 6 months later.
“Four diagno-ses were initially reported as variants of uncertain significance but upgraded with additional data, including publication of another novel gene, IREB2, 6 months later.20,21”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587 · see citing works
The role of iron in brain ageing and neurodegenerative disorders
Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R., & Zecca, L. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70117-6 · Cited by 1,819 · see citing works
Organelle isolation: functional mitochondria from mouse liver, muscle and cultured filroblasts
Frezza, C., Cipolat, S., & Scorrano, L. (2007) · Nature Protocols · doi:10.1038/nprot.2006.478 · Cited by 1,188 · see citing works
Clinical application of whole-exome sequencing across clinical indications
Retterer, K., Juusola, J., Cho, M. T., Vitazka, P., Millan, F., Gibellini, F., Vertino-Bell, A., Smaoui, N., Neidich, J., Monaghan, K. G., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.148 · Cited by 1,036 · see citing works
Kakhlon, O., & Cabantchik, Z. I. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)01006-7 · Cited by 839 · see citing works
LaVaute, T., Smith, S., Cooperman, S., Iwai, K., Land, W., Meyron-Holtz, E., Drake, S. K., Miller, G., Abu-Asab, M., Tsokos, M., et al. (2001) · Nature Genetics · doi:10.1038/84859 · Cited by 509 · see citing works
Self-citationIron metabolism in the CNS: implications for neurodegenerative diseases
Rouault, T. A. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3453 · Cited by 496 · see citing works
Self-citationMeyron‐Holtz, E. G., Ghosh, M. C., Iwai, K., LaVaute, T., Brazzolotto, X., Berger, U. V., Land, W., Ollivierre‐Wilson, H., Grinberg, A., Love, P., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600041 · Cited by 408 · see citing works
Self-citationTong, W.-H., & Rouault, T. A. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.003 · Cited by 294 · see citing works
Self-citationCooperman, S. S., Meyron-Holtz, E. G., Olivierre-Wilson, H., Ghosh, M. C., McConnell, J. P., & Rouault, T. A. (2005) · Blood · doi:10.1182/blood-2004-12-4703 · Cited by 235 · see citing works
Self-citationCochaperone Binding to LYR Motifs Confers Specificity of Iron Sulfur Cluster Delivery
Maio, N., Singh, A., Uhrigshardt, H., Saxena, N., Tong, W.-H., & Rouault, T. A. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.015 · Cited by 167 · see citing works
Self-citationIron dysregulation in Huntington's disease
Müller, M., & Leavitt, B. R. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12739 · Cited by 122 · see citing works
Dietrich, P., Johnson, I. M., Alli, S., & Dragatsis, I. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006846 · Cited by 103 · see citing works
Ghosh, M. C., Tong, W.-H., Zhang, D., Ollivierre, H., Singh, A., Krishna, M. C., Mitchell, J. B., & Rouault, T. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805361105 · Cited by 93 · see citing works
Self-citationIron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins
Ghosh, M. C., Zhang, D., & Rouault, T. A. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.02.026 · Cited by 63 · see citing works
Self-citationGaly, B., Hölter, S. M., Klopstock, T., Ferring–Appel, D., Becker, L., Kaden, S., Wurst, W., Gröne, H., & Hentze, M. W. (2006) · Nature Genetics · doi:10.1038/ng0906-967 · Cited by 62 · see citing works
Zumbrennen‐Bullough, K. B., Becker, L., Garrett, L., Hölter, S. M., Calzada‐Wack, J., Moßbrugger, I., Quintanilla-Fend, L., Rácz, I., Rathkolb, B., Klopstock, T., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098072 · Cited by 60 · see citing works
Sánchez‐Castañeda, C., Squitieri, F., Paola, M. D., Dayan, M., Petrollini, M., & Sabatini, U. (2014) · Human Brain Mapping · doi:10.1002/hbm.22612 · Cited by 46 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Kakhlon, O, Cabantchik, ZI. The labile iron pool: characterization, measurement, and participation in cellular processes(1). Free Radic Biol Med 2002; 33: 1037-46.
Cited by
Sorted by citations
Iron metabolism and iron disorders revisited in the hepcidin era
Camaschella, C., Nai, A., & Silvestri, L. (2020) · Haematologica · doi:10.3324/haematol.2019.232124 · Cited by 734 · see citing works
Australian Genomics Health Alliance Acute Care Flagship, Lunke, S., Eggers, S., Wilson, M., Patel, C., Barnett, C. P., Pinner, J., Sandaradura, S. A., Buckley, M. F., Krzesinski, E. I., et al. (2020) · JAMA · doi:10.1001/jama.2020.7671 · Cited by 239 · see citing works
Epigenome-wide association study of alcohol use disorder in five brain regions
Zillich, L., Frank, J., Streit, F., Friske, M. M., Foo, J. C., Sirignano, L., Heilmann-Heimbach, S., Dukal, H., Degenhardt, F., Hoffmann, P., et al. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01228-7 · Cited by 36 · see citing works
IREB2-associated neurodegeneration.
Cooper, M. S., Stark, Z., Lunke, S., Zhao, T., & Amor, D. J. (2019) · Brain · doi:10.1093/brain/awz183 · Cited by 28 · see citing works
- Authors
- Costain, G., Ghosh, M. C., Maio, N., Carnevale, A., Si, Y. C., Rouault, T. A., & Yoon, G.
- Affiliations
- University of Toronto (CA)
- National Institutes of Health (US)
- Hospital for Sick Children (CA)
- Corresponding author
- Yoon, Grace
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-03-26
- Volume
- 142
- Issue
- 5
- Pages
- 1195-1202
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6487337
- OpenAlex
- W2924893660
- Cited by
- 55
- References
- 18
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 10 · 2023: 7 · 2022: 7 · 2021: 9 · 2020: 10 · 2019: 3
- FWCI
- 5.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Child Health and Human Development
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- IRP2, IREB2, iron homeostasis, neurodegeneration, choreoathetosis, movement disorders, erythropoietic protoporphyria, anemia, iron deficiency, post-transcriptional regulation, mitochondrial dysfunction, loss-of-function mutations, lentiviral gene therapy, lymphoblastoid cell lines, mouse model
- MeSH terms
- Adolescent, Cell Line, Transformed, Humans, Male, Genetic Variation, Neurodegenerative Diseases, Iron Regulatory Protein 2
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
