35 results on '"Groet J"'
Search Results
2. Microarray transcript profiling distinguishes the transient from the acute forms of megakaryoblastic leukemia (M7) in Down's syndrome
- Author
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Mcelwaine, S, Mulligan, C, Groet, J, Spinelli, M, Rinaldi, A, Denyer, G, Mensah, A, Cavani, S, Baldo, C, DAGNA BRICARELLI, F, Hann, I, Basso, Giuseppe, Cotter, Fe, and Nizetic, D.
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transient myeloproliferative disorder ,Down's syndrome,microarray,transient myeloproliferative disorder,acute megakaryoblastic leukaemia (M7) ,acute megakaryoblastic leukaemia (M7) ,Down's syndrome ,microarray - Published
- 2004
3. Candidate Genes for the 11Q Abnormality in Chronic Lymphocytic Leukaemia (CLL)
- Author
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Auer, RL, primary, Bertoni, F, additional, McElwaine, S, additional, Groet, J, additional, Jones, C, additional, Fegan, CD, additional, and Cotter, FE, additional
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- 2002
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4. Narrowing of the region of allelic loss in 21q11-21 in squamous non-small cell lung carcinoma and cloning of a novel ubiquitin-specific protease gene from the deleted segment
- Author
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Groet, J�rgen, primary, Ives, Jane H., additional, Jones, Tania A., additional, Danton, Malcolm, additional, Flomen, Rachel H., additional, Sheer, Denise, additional, Hra??an, Reno, additional, Paveli?, Kre?imir, additional, and Ni?eti?, Dean, additional
- Published
- 2000
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5. Two Sequence-Ready Contigs Spanning the Two Copies of a 200-kb Duplication on Human 21q: Partial Sequence and Polymorphisms
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Potier, M.-C, primary, Dutriaux, A, additional, Orti, R, additional, Groet, J, additional, Gibelin, N, additional, Karadima, G, additional, Lutfalla, G, additional, Lynn, A, additional, Van Broeckhoven, C, additional, Chakravarti, A, additional, Petersen, M, additional, Nizetic, D, additional, Delabar, J, additional, and Rossier, J, additional
- Published
- 1998
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6. Rieger syndrome locus: a new reciprocal translocation t(4;12)(q25;q15) and a deletion del(4)(q25q27) both break between markers D4S2945 and D4S193.
- Author
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Flomen, R H, primary, Gorman, P A, additional, Vatcheva, R, additional, Groet, J, additional, Barisic, I, additional, Ligutic, I, additional, Sheer, D, additional, and Nizetic, D, additional
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- 1997
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7. Bacterial contig map of the 21q11 region associated with Alzheimer's disease and abnormal myelopoiesis in Down syndrome.
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Groet, J, Ives, J H, South, A P, Baptista, P R, Jones, T A, Yaspo, M L, Lehrach, H, Potier, M C, Van Broeckhoven, C, and Nizetić, D
- Abstract
We present a high-resolution bacterial contig map of 3.4 Mb of genomic DNA in human chromosome 21q11-q21, encompassing the region of elevated disomic homozygosity in Down Syndrome-associated abnormal myelopoiesis and leukemia, as well as the markers, which has shown a strong association with Alzheimer's Disease that has never been explained. The map contains 89 overlapping PACs, BACs, or cosmids in three contigs (850, 850, and 1500 kb) with two gaps (one of 140-210 kb and the second <5 kb). To date, eight transcribed sequences derived by cDNA selection, exon trapping, and/or global EST sequencing have been positioned onto the map, and the only two genes so far mapped to this cytogenetic region, STCH and RIP140 have been precisely localized. This work converts a further 10% of chromosome 21q into a high-resolution bacterial contig map, which will be the physical basis for the long-range sequencing of this region. The map will also enable positional derivation of new transcribed sequences, as well as new polymorphic probes, that will help in elucidation of the role the genes in this region may play in abnormal myelopoiesis and leukemia associated with trisomy 21 and Alzheimer's Disease.
- Published
- 1998
8. Transchromosomic cell model of Down syndrome shows aberrant migration, adhesion and proteome response to extracellular matrix
- Author
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Cotter Finbarr E, Groet Jürgen, Veltman Joris, Hoischen Alex, Burt Emma, Delom Frédéric, and Nizetic Dean
- Subjects
Cytology ,QH573-671 - Abstract
Abstract Background Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic birth defect. Congenital heart defects (CHD) are seen in 40% of DS children, and >50% of all atrioventricular canal defects in infancy are caused by trisomy 21, but the causative genes remain unknown. Results Here we show that aberrant adhesion and proliferation of DS cells can be reproduced using a transchromosomic model of DS (mouse fibroblasts bearing supernumerary HSA21). We also demonstrate a deacrease of cell migration in transchromosomic cells independently of their adhesion properties. We show that cell-autonomous proteome response to the presence of Collagen VI in extracellular matrix is strongly affected by trisomy 21. Conclusion This set of experiments establishes a new model system for genetic dissection of the specific HSA21 gene-overdose contributions to aberrant cell migration, adhesion, proliferation and specific proteome response to collagen VI, cellular phenotypes linked to the pathogenesis of CHD.
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- 2009
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9. Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels.
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Murray A, Gough G, Cindrić A, Vučković F, Koschut D, Borelli V, Petrović DJ, Bekavac A, Plećaš A, Hribljan V, Brunmeir R, Jurić J, Pučić-Baković M, Slana A, Deriš H, Frkatović A, Groet J, O'Brien NL, Chen HY, Yeap YJ, Delom F, Havlicek S, Gammon L, Hamburg S, Startin C, D'Souza H, Mitrečić D, Kero M, Odak L, Krušlin B, Krsnik Ž, Kostović I, Foo JN, Loh YH, Dunn NR, de la Luna S, Spector T, Barišić I, Thomas MSC, Strydom A, Franceschi C, Lauc G, Krištić J, Alić I, and Nižetić D
- Subjects
- Adult, Humans, Aging, Cell Differentiation, Dyrk Kinases, Down Syndrome genetics, Induced Pluripotent Stem Cells
- Abstract
Background: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down., Methods: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids., Findings: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage., Interpretation: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies., Funding: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements"., Competing Interests: Declaration of interests GL is the founder and owner of Genos Ltd., a private research organisation that specialises in high-throughput glycomic analyses and has several patents in this field and is also a shareholder in GlycanAge Ltd., a company that sells the GlycanAge test of biological age. AC, FV, JJ, MPB, ASla, HD, AF, DP and JK are employees of Genos Ltd. AStr has served on the Advisory Boards of AC Immune and ProMIS Neuroscience, and is a past president of the Trisomy21 Research Society. TS is the scientific co-founder and a shareholder of Zoe Ltd., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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10. Correction: Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
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Alić I, Goh PA, Murray A, Portelius E, Gkanatsiou E, Gough G, Mok KY, Koschut D, Brunmeir R, Yeap YJ, O'Brien NL, Groet J, Shao X, Havlicek S, Dunn NR, Kvartsberg H, Brinkmalm G, Hithersay R, Startin C, Hamburg S, Phillips M, Pervushin K, Turmaine M, Wallon D, Rovelet-Lecrux A, Soininen H, Volpi E, Martin JE, Foo JN, Becker DL, Rostagno A, Ghiso J, Krsnik Ž, Šimić G, Kostović I, Mitrečić D, Francis PT, Blennow K, Strydom A, Hardy J, Zetterberg H, and Nižetić D
- Published
- 2021
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11. Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.
- Author
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Alić I, Goh PA, Murray A, Portelius E, Gkanatsiou E, Gough G, Mok KY, Koschut D, Brunmeir R, Yeap YJ, O'Brien NL, Groet J, Shao X, Havlicek S, Dunn NR, Kvartsberg H, Brinkmalm G, Hithersay R, Startin C, Hamburg S, Phillips M, Pervushin K, Turmaine M, Wallon D, Rovelet-Lecrux A, Soininen H, Volpi E, Martin JE, Foo JN, Becker DL, Rostagno A, Ghiso J, Krsnik Ž, Šimić G, Kostović I, Mitrečić D, Francis PT, Blennow K, Strydom A, Hardy J, Zetterberg H, and Nižetić D
- Subjects
- Amyloid Precursor Protein Secretases genetics, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides metabolism, Aspartic Acid Endopeptidases genetics, Aspartic Acid Endopeptidases metabolism, Brain metabolism, Genes, Suppressor, Humans, Organoids metabolism, Trisomy, Alzheimer Disease genetics, Down Syndrome genetics
- Abstract
A population of more than six million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases., (© 2020. The Author(s).)
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- 2021
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12. RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia.
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Koschut D, Ray D, Li Z, Giarin E, Groet J, Alić I, Kham SK, Chng WJ, Ariffin H, Weinstock DM, Yeoh AE, Basso G, and Nižetić D
- Subjects
- Animals, Cytokines physiology, Humans, Janus Kinase 2 genetics, Janus Kinase 2 physiology, Mice, Phosphatidylinositol 3-Kinases physiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Protein Tyrosine Phosphatase, Non-Receptor Type 11 physiology, Receptors, Cytokine genetics, Signal Transduction physiology, TOR Serine-Threonine Kinases physiology, ras Proteins antagonists & inhibitors, ras Proteins genetics, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, ras Proteins physiology
- Abstract
Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS-ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK-signaling, prevented TSLP-induced RAS-GTP boost. Cytotoxicity assays on primary clinical DS-ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS-inhibitor or PTPN11-inhibitor, but not PI3K/JAK-inhibitors, suggesting a unified treatment target for up to 80% of DS-ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein-activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient-stratification strategy for precision therapy in high-risk ALL.
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- 2021
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13. Modeling Down syndrome in cells: From stem cells to organoids.
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Gough G, O'Brien NL, Alic I, Goh PA, Yeap YJ, Groet J, Nizetic D, and Murray A
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- Animals, Humans, CRISPR-Cas Systems, Down Syndrome, Models, Biological, Organoids, Pluripotent Stem Cells
- Abstract
Down Syndrome (DS) is a complex chromosomal disorder, with neurological issues, featuring among the symptoms. Primary neuronal cells and tissues are extremely useful, but limited both in supply and experimental manipulability. To better understand the cellular, molecular and pathological mechanisms involved in DS neurodevelopment and neurodegeneration, a range of different cellular models have been developed over the years including human: mouse hybrid cells, transchromosomic mouse embryonic stem cells (ESCs) and human ESC and induced pluripotent stem cells derived from different sources. All of these model systems have provided useful information in the study of DS. Furthermore, different technologies to genetically modify or correct trisomy of either single genes or the whole chromosome have been developed using these cellular models. New techniques and protocols to allow better modeling of cellular mechanisms and disease processes are being developed and the use of cerebral organoids offers great promise for future research into the neural phenotypes seen in DS., (© 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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14. Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome.
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Strydom A, Heslegrave A, Startin CM, Mok KY, Hardy J, Groet J, Nizetic D, and Zetterberg H
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- Adolescent, Adult, Age Factors, Aged, Dementia blood, Dementia diagnosis, Dementia etiology, Female, Humans, Male, Middle Aged, Statistics, Nonparametric, Young Adult, Down Syndrome complications, Nerve Degeneration blood, Nerve Degeneration etiology, Neurofilament Proteins blood
- Abstract
Background: Down syndrome (DS) may be considered a genetic form of Alzheimer's disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions., Methods: We measured blood NF-L concentrations in 100 adults with DS using Simoa NF-light® assays, and we examined relationships with age as well as cross-sectional and longitudinal dementia diagnosis., Results: NF-L concentrations increased with age (Spearman's rho = 0.789, p < 0.001), with a steep increase after age 40, and they were predictive of dementia status (p = 0.022 adjusting for age, sex, and APOE4), but they showed no relationship with long-standing epilepsy or premorbid ability. Baseline NF-L concentrations were associated with longitudinal dementia status., Conclusions: NF-L is a biomarker for neurodegeneration in DS with potential for use in future clinical trials to prevent or delay dementia.
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- 2018
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15. Intracerebral haemorrhage in Down syndrome: protected or predisposed?
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Buss L, Fisher E, Hardy J, Nizetic D, Groet J, Pulford L, and Strydom A
- Abstract
Down syndrome (DS), which arises from trisomy of chromosome 21, is associated with deposition of large amounts of amyloid within the central nervous system. Amyloid accumulates in two compartments: as plaques within the brain parenchyma and in vessel walls of the cerebral microvasculature. The parenchymal plaque amyloid is thought to result in an early onset Alzheimer's disease (AD) dementia, a phenomenon so common amongst people with DS that it could be considered a defining feature of the condition. The amyloid precursor protein ( APP) gene lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset AD. In contrast, intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. We review recent epidemiological data on stroke (including haemorrhagic stroke) in order to make comparisons with a rare form of familial AD due to duplication (i.e. having three copies) of the APP region on chromosome 21, here called 'dup-APP', which is associated with more frequent and severe ICH. We conclude that although people with DS are at increased risk of ICH, this is less common than in dup-APP, suggesting the presence of mechanisms that act protectively. We review these mechanisms and consider comparative research into DS and dup-APP that may yield further pathophysiological insight.
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- 2016
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16. The importance of understanding individual differences in Down syndrome.
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Karmiloff-Smith A, Al-Janabi T, D'Souza H, Groet J, Massand E, Mok K, Startin C, Fisher E, Hardy J, Nizetic D, Tybulewicz V, and Strydom A
- Abstract
In this article, we first present a summary of the general assumptions about Down syndrome (DS) still to be found in the literature. We go on to show how new research has modified these assumptions, pointing to a wide range of individual differences at every level of description. We argue that, in the context of significant increases in DS life expectancy, a focus on individual differences in trisomy 21 at all levels-genetic, cellular, neural, cognitive, behavioral, and environmental-constitutes one of the best approaches for understanding genotype/phenotype relations in DS and for exploring risk and protective factors for Alzheimer's disease in this high-risk population.
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- 2016
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17. Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration.
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Murray A, Letourneau A, Canzonetta C, Stathaki E, Gimelli S, Sloan-Bena F, Abrehart R, Goh P, Lim S, Baldo C, Dagna-Bricarelli F, Hannan S, Mortensen M, Ballard D, Syndercombe Court D, Fusaki N, Hasegawa M, Smart TG, Bishop C, Antonarakis SE, Groet J, and Nizetic D
- Subjects
- Animals, Cells, Cultured, Fibroblasts cytology, Humans, Mitochondria genetics, Aging physiology, Cell Differentiation physiology, Down Syndrome genetics, Induced Pluripotent Stem Cells cytology, Neurons cytology
- Abstract
Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21., (© 2015 AlphaMed Press.)
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- 2015
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18. Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations.
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Nikolaev SI, Garieri M, Santoni F, Falconnet E, Ribaux P, Guipponi M, Murray A, Groet J, Giarin E, Basso G, Nizetic D, and Antonarakis SE
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- Child, Chromatin chemistry, DNA Mutational Analysis, Down Syndrome metabolism, Female, Gene Deletion, Gene Expression Regulation, Leukemic, Humans, Lymphocytes cytology, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Receptors, Cytokine genetics, Down Syndrome genetics, Janus Kinase 2 genetics, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, ras Proteins metabolism
- Abstract
Children with Down syndrome (DS) and acute lymphoblastic leukaemia (ALL) have poorer survival and more relapses than non-DS children with ALL, highlighting an urgent need for deeper mechanistic understanding of DS-ALL. Here, using full-exome or cancer genes-targeted sequencing of 42 ALL samples from 39 DS patients, we uncover driver mutations in RAS, (KRAS and NRAS) recurring to a similar extent (15/42) as JAK2 (12/42) mutations or P2RY8-CRLF2 fusions (14/42). RAS mutations are almost completely mutually exclusive with JAK2 mutations (P=0.016), driving a combined total of two-thirds of analysed cases. Clonal architecture analysis reveals that both RAS and JAK2 drove sub-clonal expansions primarily initiated by CRLF2 rearrangements, and/or mutations in chromatin remodellers and lymphocyte differentiation factors. Remarkably, in 2/3 relapsed cases, there is a switch from a primary JAK2- or PTPN11-mutated sub-clone to a RAS-mutated sub-clone in relapse. These results provide important new insights informing the patient stratification strategies for targeted therapeutic approaches for DS-ALL.
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- 2014
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19. Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome.
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Nikolaev SI, Santoni F, Vannier A, Falconnet E, Giarin E, Basso G, Hoischen A, Veltman JA, Groet J, Nizetic D, and Antonarakis SE
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- Disease Progression, Down Syndrome complications, Exome genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Genomic Instability genetics, High-Throughput Nucleotide Sequencing methods, Humans, Infant, Infant, Newborn, Leukemia, Megakaryoblastic, Acute complications, Leukemia, Megakaryoblastic, Acute pathology, Microarray Analysis, Myeloproliferative Disorders complications, Myeloproliferative Disorders pathology, Polymorphism, Single Nucleotide, Transcriptome, Cell Transformation, Neoplastic genetics, Down Syndrome genetics, Leukemia, Megakaryoblastic, Acute genetics, Myeloproliferative Disorders genetics
- Abstract
Some neonates with Down syndrome (DS) are diagnosed with self-regressing transient myeloproliferative disorder (TMD), and 20% to 30% of those progress to acute megakaryoblastic leukemia (AMKL). We performed exome sequencing in 7 TMD/AMKL cases and copy-number analysis in these and 10 additional cases. All TMD/AMKL samples contained GATA1 mutations. No exome-sequenced TMD/AMKL sample had other recurrently mutated genes. However, 2 of 5 TMD cases, and all AMKL cases, showed mutations/deletions other than GATA1, in genes proven as transformation drivers in non-DS leukemia (EZH2, APC, FLT3, JAK1, PARK2-PACRG, EXT1, DLEC1, and SMC3). One patient at the TMD stage revealed 2 clonal expansions with different GATA1 mutations, of which 1 clone had an additional driver mutation. Interestingly, it was the other clone that gave rise to AMKL after accumulating mutations in 7 other genes. Data suggest that GATA1 mutations alone are sufficient for clonal expansions, and additional driver mutations at the TMD stage do not necessarily predict AMKL progression. Later in infancy, leukemic progression requires "third-hit driver" mutations/somatic copy-number alterations found in non-DS leukemias. Putative driver mutations affecting WNT (wingless-related integration site), JAK-STAT (Janus kinase/signal transducer and activator of transcription), or MAPK/PI3K (mitogen-activated kinase/phosphatidylinositol-3 kinase) pathways were found in all cases, aberrant activation of which converges on overexpression of MYC.
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- 2013
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20. Tumorigenesis in Down's syndrome: big lessons from a small chromosome.
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Nižetić D and Groet J
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- Aging genetics, Cellular Senescence, Chromosomal Instability, Down Syndrome complications, Down Syndrome immunology, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Humans, Neoplasms blood supply, Neovascularization, Pathologic, Oncogenes, Stem Cells physiology, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 21 genetics, Down Syndrome genetics, Neoplasms epidemiology, Neoplasms genetics
- Abstract
If assessed by a number of criteria for cancer predisposition, Down's syndrome (DS) should be an overwhelmingly cancer-prone condition. Although childhood leukaemias occur more frequently in DS, paradoxically, individuals with DS have a markedly lower incidence of most solid tumours. Understanding the mechanisms that are capable of overcoming such odds could potentially open new routes for cancer prevention and therapy. In this Opinion article, we discuss recent reports that suggest unique and only partially understood mechanisms behind this paradox, including tumour repression, anti-angiogenic effects and stem cell ageing and availability.
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- 2012
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21. Amplified segment in the 'Down syndrome critical region' on HSA21 shared between Down syndrome and euploid AML-M0 excludes RUNX1, ERG and ETS2.
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Canzonetta C, Hoischen A, Giarin E, Basso G, Veltman JA, Nacheva E, Nizetic D, and Groet J
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- Adolescent, Adult, Female, Humans, Male, Transcriptional Regulator ERG, Core Binding Factor Alpha 2 Subunit genetics, Down Syndrome genetics, Genetic Loci, Leukemia, Myeloid, Acute genetics, Proto-Oncogene Protein c-ets-2 genetics, Trans-Activators genetics
- Abstract
Children with Down syndrome have a 20- to 50-fold increased risk of acute lymphocytic or myeloid leukaemia. Whole or partial gains of chromosome 21 have been described in multiple childhood leukaemias, and have recently been reported as a likely primary event in B-precursor-acute lymphoblastic leukaemia. It is unclear which amplified gene(s) on chromosome 21 play a key role in leukaemia progression. We describe a minimal amplified segment within the so-called 'Down syndrome critical region' shared between two cases of AML-M0; a Down syndrome, and a constitutionally normal individual. Interestingly, the amplified region does not include the oncogenes RUNX1, ETS2 and ERG., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2012
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22. Transchromosomic cell model of Down syndrome shows aberrant migration, adhesion and proteome response to extracellular matrix.
- Author
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Delom F, Burt E, Hoischen A, Veltman J, Groet J, Cotter FE, and Nizetic D
- Abstract
Background: Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic birth defect. Congenital heart defects (CHD) are seen in 40% of DS children, and >50% of all atrioventricular canal defects in infancy are caused by trisomy 21, but the causative genes remain unknown., Results: Here we show that aberrant adhesion and proliferation of DS cells can be reproduced using a transchromosomic model of DS (mouse fibroblasts bearing supernumerary HSA21). We also demonstrate a deacrease of cell migration in transchromosomic cells independently of their adhesion properties. We show that cell-autonomous proteome response to the presence of Collagen VI in extracellular matrix is strongly affected by trisomy 21., Conclusion: This set of experiments establishes a new model system for genetic dissection of the specific HSA21 gene-overdose contributions to aberrant cell migration, adhesion, proliferation and specific proteome response to collagen VI, cellular phenotypes linked to the pathogenesis of CHD.
- Published
- 2009
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23. Quantitative proteomics characterization of a mouse embryonic stem cell model of Down syndrome.
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Wang Y, Mulligan C, Denyer G, Delom F, Dagna-Bricarelli F, Tybulewicz VL, Fisher EM, Griffiths WJ, Nizetic D, and Groet J
- Subjects
- Animals, Blotting, Western, Cell Line, Chromosomes, Human, Pair 21 metabolism, Disease Models, Animal, Fetus metabolism, Fetus pathology, Humans, Mice, Peptides metabolism, Proteins metabolism, Reproducibility of Results, Staining and Labeling, Down Syndrome metabolism, Embryonic Stem Cells metabolism, Proteomics
- Abstract
Down syndrome, caused by the trisomy of chromosome 21, is a complex condition characterized by a number of phenotypic features, including reduced neuron number and synaptic plasticity, early Alzheimer disease-like neurodegeneration, craniofacial dysmorphia, heart development defects, increased incidence of childhood leukemia, and powerful suppression of the incidence of most solid tumors. Mouse models replicate a number of these phenotypes. The Tc1 Down syndrome model was constructed by introducing a single supernumerary human chromosome 21 into a mouse embryonic stem cell, and it reproduces a large number of Down syndrome phenotypes including heart development defects. However, little is still known about the developmental onset of the trisomy 21-induced mechanisms behind these phenotypes or the proteins that are responsible for them. This study determined the proteomic differences that are present in undifferentiated embryonic stem cells and are caused by an additional human chromosome 21. A total of 1661 proteins were identified using two-dimensional liquid chromatography followed by tandem mass spectrometry from whole embryonic stem cell lysates. Using isobaric tags for relative and absolute quantification, we found 52 proteins that differed in expression by greater than two standard deviations from the mean when an extra human chromosome 21 was present. Of these, at least 11 have a possible functional association with a Down syndrome phenotype or a human chromosome 21-encoded gene. This study also showed that quantitative protein expression differences in embryonic stem cells can persist to adult mouse as well as reproduce in human Down syndrome fetal tissue. This indicates that changes that are determined in embryonic stem cells of Down syndrome could potentially identify proteins that are involved in phenotypes of Down syndrome, and it shows that these cell lines can be used for the purpose of studying these pathomechanisms.
- Published
- 2009
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24. Megakaryocyte hyperproliferation without GATA1 mutation in foetal liver of a case of Down syndrome with hydrops foetalis.
- Author
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De Vita S, Devoy A, Groet J, Kruslin B, Kuzmić-Prusac I, and Nizetić D
- Subjects
- Cell Proliferation, Female, GATA1 Transcription Factor genetics, Humans, Infant, Newborn, Mutation, Spleen pathology, Down Syndrome pathology, Hydrops Fetalis pathology, Megakaryocytes pathology
- Published
- 2008
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- View/download PDF
25. DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.
- Author
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Canzonetta C, Mulligan C, Deutsch S, Ruf S, O'Doherty A, Lyle R, Borel C, Lin-Marq N, Delom F, Groet J, Schnappauf F, De Vita S, Averill S, Priestley JV, Martin JE, Shipley J, Denyer G, Epstein CJ, Fillat C, Estivill X, Tybulewicz VL, Fisher EM, Antonarakis SE, and Nizetic D
- Subjects
- Animals, Cell Differentiation, Disease Models, Animal, Down Syndrome genetics, Down Syndrome pathology, Embryonic Stem Cells physiology, Gene Expression Regulation, Developmental, Humans, Mice, Mice, Transgenic, Pluripotent Stem Cells pathology, Pluripotent Stem Cells physiology, Protein Serine-Threonine Kinases genetics, Protein-Tyrosine Kinases genetics, Quantitative Trait Loci, Repressor Proteins genetics, Dyrk Kinases, Down Syndrome metabolism, Embryonic Stem Cells pathology, Gene Dosage, Protein Serine-Threonine Kinases physiology, Protein-Tyrosine Kinases physiology, Repressor Proteins physiology
- Abstract
Down syndrome (DS) is the most common cause of mental retardation. Many neural phenotypes are shared between DS individuals and DS mouse models; however, the common underlying molecular pathogenetic mechanisms remain unclear. Using a transchromosomic model of DS, we show that a 30%-60% reduced expression of Nrsf/Rest (a key regulator of pluripotency and neuronal differentiation) is an alteration that persists in trisomy 21 from undifferentiated embryonic stem (ES) cells to adult brain and is reproducible across several DS models. Using partially trisomic ES cells, we map this effect to a three-gene segment of HSA21, containing DYRK1A. We independently identify the same locus as the most significant eQTL controlling REST expression in the human genome. We show that specifically silencing the third copy of DYRK1A rescues Rest levels, and we demonstrate altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1A mouse. We reveal that undifferentiated trisomy 21 ES cells show DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping recently reported downstream effects of Rest +/-. They produce embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 and a strongly reduced neuroectodermal progenitor compartment. Our results suggest that DYRK1A-mediated deregulation of REST is a very early pathological consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to DS pathology and new rationales for therapeutic approaches.
- Published
- 2008
- Full Text
- View/download PDF
26. An additional human chromosome 21 causes suppression of neural fate of pluripotent mouse embryonic stem cells in a teratoma model.
- Author
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Mensah A, Mulligan C, Linehan J, Ruf S, O'Doherty A, Grygalewicz B, Shipley J, Groet J, Tybulewicz V, Fisher E, Brandner S, and Nizetic D
- Subjects
- Animals, Astrocytes metabolism, Astrocytes pathology, Cell Differentiation, Cell Line, Fluorescent Antibody Technique, Glial Fibrillary Acidic Protein genetics, Glial Fibrillary Acidic Protein metabolism, Humans, Mice, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Neural Plate metabolism, Neural Plate pathology, Neurons pathology, Pluripotent Stem Cells pathology, Reverse Transcriptase Polymerase Chain Reaction, Teratoma metabolism, Teratoma pathology, Tubulin genetics, Tubulin metabolism, Chromosomes, Human, Pair 21 genetics, Neurons metabolism, Pluripotent Stem Cells metabolism, Teratoma genetics
- Abstract
Background: Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is the most common genetic cause of mental retardation in humans. Among complex phenotypes, it displays a number of neural pathologies including smaller brain size, reduced numbers of neurons, reduced dendritic spine density and plasticity, and early Alzheimer-like neurodegeneration. Mouse models for DS show behavioural and cognitive defects, synaptic plasticity defects, and reduced hippocampal and cerebellar neuron numbers. Early postnatal development of both human and mouse-model DS shows the reduced capability of neuronal precursor cells to generate neurons. The exact molecular cause of this reduction, and the role played by increased dosage of individual HSA21 genes, remain unknown., Results: We have subcutaneously injected mouse pluripotent ES cells containing a single freely segregating supernumerary human chromosome 21 (HSA21) into syngeneic mice, to generate transchromosomic teratomas. Transchromosomic cells and parental control cells were injected into opposite flanks of thirty mice in three independent experiments. Tumours were grown for 30 days, a time-span equivalent to combined intra-uterine, and early post-natal mouse development. When paired teratomas from the same animals were compared, transchromosomic tumours showed a three-fold lower percentage of neuroectodermal tissue, as well as significantly reduced mRNA levels for neuron specific (Tubb3) and glia specific (Gfap) genes, relative to euploid controls. Two thirds of transchromosomic tumours also showed a lack of PCR amplification with multiple primers specific for HSA21, which were present in the ES cells at the point of injection, thus restricting a commonly retained trisomy to less than a third of HSA21 genes., Conclusion: We demonstrate that a supernumerary chromosome 21 causes Inhibition of Neuroectodermal DIfferentiation (INDI) of pluripotent ES cells. The data suggest that trisomy of less than a third of HSA21 genes, in two chromosomal regions, might be sufficient to cause this effect.
- Published
- 2007
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27. Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome.
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De Vita S, Mulligan C, McElwaine S, Dagna-Bricarelli F, Spinelli M, Basso G, Nizetic D, and Groet J
- Subjects
- Base Sequence, Down Syndrome immunology, Enzyme Activation, Gene Deletion, Humans, Leukemia, Megakaryoblastic, Acute complications, Molecular Sequence Data, Protein-Tyrosine Kinases genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Down Syndrome genetics, Janus Kinase 3 genetics, Leukemia, Megakaryoblastic, Acute genetics, Mutation
- Abstract
Acquired mutations activating Janus kinase 3 (jak3) have been reported in Down syndrome (DS) and non-DS patients with acute megakaryoblastic leukaemia (AMKL). This highlighted jak3-activation as an important event in the pathogenesis of AMKL, and predicted inhibitors of jak3 as conceptual therapeutics for AMKL. Of 16 DS-transient myeloproliferative disorder (TMD)/AMKL patients tested, seven showed JAK3 mutations. Three mutations deleted the kinase (JH1) domain, abolishing the main function of jak3. Another patient displayed a mutation identical to a previously reported inherited loss-of-function causing severe combined immunodeficiency. Our data suggest that both gain-, and loss-of function mutations of jak3 can be acquired in DS-TMD/AMKL.
- Published
- 2007
- Full Text
- View/download PDF
28. Independent clones at separable stages of differentiation, bearing different GATA1 mutations, in the same TMD patient with Down syndrome.
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Groet J, Mulligan C, Spinelli M, Serra A, McElwaine S, Cotter FE, Dagna-Bricarelli F, Saglio G, Basso G, and Nizetic D
- Subjects
- Antigens, CD34 biosynthesis, Cell Differentiation physiology, Clone Cells, Erythroid-Specific DNA-Binding Factors, Female, GATA1 Transcription Factor, Humans, Infant, Newborn, Megakaryocytes physiology, Mutation, Reverse Transcriptase Polymerase Chain Reaction, DNA-Binding Proteins genetics, Down Syndrome complications, Down Syndrome genetics, Myeloproliferative Disorders complications, Myeloproliferative Disorders genetics, Transcription Factors genetics
- Published
- 2005
- Full Text
- View/download PDF
29. Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker.
- Author
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McElwaine S, Mulligan C, Groet J, Spinelli M, Rinaldi A, Denyer G, Mensah A, Cavani S, Baldo C, Dagna-Bricarelli F, Hann I, Basso G, Cotter FE, and Nizetic D
- Subjects
- Acute Disease, Cell Cycle Proteins genetics, Child, Preschool, Cyclin-Dependent Kinase Inhibitor p18, Diagnosis, Differential, Female, Genetic Markers, Humans, Infant, Newborn, Male, Myeloproliferative Disorders diagnosis, N-Myc Proto-Oncogene Protein, Nuclear Proteins genetics, Oncogene Proteins genetics, Remission, Spontaneous, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins genetics, Antigens, Neoplasm genetics, Down Syndrome immunology, Leukemia, Megakaryoblastic, Acute diagnosis, Oligonucleotide Array Sequence Analysis
- Abstract
Transient myeloproliferative disorder (TMD) is a unique, spontaneously regressing neoplasia specific to Down's syndrome (DS), affecting up to 10% of DS neonates. In 20-30% of cases, it reoccurs as progressive acute megakaryoblastic leukaemia (AMKL) at 2-4 years of age. The TMD and AMKL blasts are morphologically and immuno-phenotypically identical, and have the same acquired mutations in GATA1. We performed transcript profiling of nine TMD patients comparing them with seven AMKL patients using Affymetrix HG-U133A microarrays. Similar overall transcript profiles were observed between the two conditions, which were only separable by supervised clustering. Taqman analysis on 10 TMD and 10 AMKL RNA samples verified the expression of selected differing genes, with statistical significance (P < 0.05) by Student's t-test. The Taqman differences were also reproduced on TMD and AMKL blasts sorted by a fluorescence-activated cell sorter. Among the significant differences, CDKN2C, the effector of GATA1-mediated cell cycle arrest, was increased in AMKL but not TMD, despite the similar level of GATA1. In contrast, MYCN (neuroblastoma-derived oncogene) was expressed in TMD at a significantly greater level than in AMKL. MYCN has not previously been described in leukaemogenesis. Finally, the tumour antigen PRAME was identified as a specific marker for AMKL blasts, with no expression in TMD. This study provides markers discriminating TMD from AMKL-M7 in DS. These markers have the potential as predictive, diagnostic and therapeutic targets. In addition, the study provides further clues into the pathomechanisms discerning self-regressive from the progressive phenotype.
- Published
- 2004
- Full Text
- View/download PDF
30. Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder.
- Author
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Groet J, McElwaine S, Spinelli M, Rinaldi A, Burtscher I, Mulligan C, Mensah A, Cavani S, Dagna-Bricarelli F, Basso G, Cotter FE, and Nizetic D
- Subjects
- Child, Preschool, Down Syndrome complications, Erythroid-Specific DNA-Binding Factors, Exons genetics, Female, GATA1 Transcription Factor, Humans, Infant, Infant, Newborn, Karyotyping, Leukemia, Myeloid complications, Male, Mutation, DNA-Binding Proteins genetics, Down Syndrome genetics, Leukemia, Myeloid genetics, Transcription Factors genetics
- Abstract
Transient myeloid disorder is a unique self-regressing neoplasia specific to Down's syndrome. The transcription factor GATA1 is needed for normal growth and maturation of erythroid cells and megakaryocytes. Mutations in GATA1 have been reported in acute megakaryoblastic leukaemia in Down's syndrome. We aimed to investigate changes in GATA1 in patients with Down's syndrome and either transient myeloid disorder (n=10) or acute megakaryoblastic leukaemia (n=6). We recorded mutations eliminating exon 2 from GATA1 in all patients with transient myeloid disorder (age 0-24 days) and in all with acute megakaryoblastic leukaemia (age 14-38 months). The range of mutations did not differ between patients with each disorder. Patients with transient myeloid disorder with mutations in GATA1 can regress spontaneously to complete remission, and mutations do not necessarily predict later acute megakaryoblastic leukaemia.
- Published
- 2003
- Full Text
- View/download PDF
31. High resolution physical mapping and identification of transcribed sequences in the Down syndrome region-2.
- Author
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Vidal-Taboada JM, Bergoñón S, Sánchez M, López-Acedo C, Groet J, Nizetic D, Egeo A, Scartezzini P, Katsanis N, Fisher EM, Delabar JM, and Oliva R
- Subjects
- Cosmids genetics, DNA, Complementary genetics, Deoxyribonuclease EcoRI metabolism, Deoxyribonucleases, Type II Site-Specific metabolism, Genetic Markers genetics, Humans, Microsatellite Repeats genetics, Molecular Sequence Data, Restriction Mapping, Transcription, Genetic genetics, Chromosome Mapping, Chromosomes, Human, Pair 21 genetics, Down Syndrome genetics
- Abstract
The identification and mapping of genes within the Down syndrome region is an important step toward a complete understanding of the pathogenesis of this disorder. The objective of the present work is to identify and map genes within the Down syndrome region-2. Chromosome 21 cosmid clones corresponding to "cosmid pockets" 121-124 have been first used as a starting material for generation of a single high resolution integrated cosmid/PAC contig with full EcoRI/SmaI restriction map. The integrated contig has been further anchored to genetic and physical maps through the positioning of 6 markers in the following order: ACTL5-D21S3-684G2T7-D21S71-D21S343-D21S 268. The entire contig covers 342 kb of the Down syndrome region-2 of chromosome 21. Subsequently, we have isolated, identified, and mapped four novel cDNAs which we have named N143, N144, CHD/333, and 90/3H1 and a potentially transcribed genomic sequence (E05133T7). Additionally, we have accurately located a previously described gene, the WRB gene, between the markers ACTL5-D21S268 within this Down Syndrome Region-2.
- Published
- 1998
- Full Text
- View/download PDF
32. Construction and analysis of a sequence-ready map in 4q25: Rieger syndrome can be caused by haploinsufficiency of RIEG, but also by chromosome breaks approximately 90 kb upstream of this gene.
- Author
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Flomen RH, Vatcheva R, Gorman PA, Baptista PR, Groet J, Barisić I, Ligutic I, and Nizetić D
- Subjects
- Base Composition, Genes, Dominant, Humans, Paired Box Transcription Factors, Sequence Deletion, Syndrome, Homeobox Protein PITX2, Abnormalities, Multiple genetics, Chromosome Breakage genetics, Chromosome Mapping, Chromosomes, Human, Pair 4 genetics, Homeodomain Proteins genetics, Nuclear Proteins, Transcription Factors genetics
- Abstract
The autosomal dominant disorder Rieger syndrome (RIEG) shows genetic heterogeneity and has a phenotype characterized by malformations of the anterior segment of the eye, failure of the periumbilical skin to involute, and dental hypoplasia. The main locus for RIEG was mapped to the 4q25-q27 chromosomal segment using a series of cytogenetic abnormalities as well as by genetic linkage to DNA markers. Recently, a bicoid-related homeobox transcription factor gene called RIEG has been cloned, characterized, and proven to cause the 4q25 linked RIEG. Its mode of action in the pathogenesis of RIEG was not conclusively proven, since most etiological mutations detected in the RIEG sequence caused amino acid substitutions or splice changes in the homeodomain. Through FISH analysis of a 460-kb sequence-ready map (PAC contig) around RIEG that we report in this paper, we demonstrate that the 4q25 linked RIEG disorder can arise from the haploid, whole-gene deletion of RIEG, but also from a translocation break 90 kb upstream from the gene. The data provide conclusive evidence that physical or functional haploinsufficiency of RIEG is the pathogenic mechanism for Rieger syndrome. The map also defines restriction fragments bearing sequences with a potential key regulatory role in the control of homeobox gene expression., (Copyright 1998 Academic Press.)
- Published
- 1998
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- View/download PDF
33. Localisation of receptor interacting protein 140 (RIP140) within 100 kb of D21S13 on 21q11, a gene-poor region of the human genome.
- Author
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Katsanis N, Ives JH, Groet J, Nizetic D, and Fisher EM
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Base Composition, Chromosome Mapping, Genes, Genetic Markers, Humans, Mice, Nuclear Receptor Interacting Protein 1, Chromosomes, Human, Pair 21 genetics, Genome, Human, Nuclear Proteins genetics, Receptors, Estrogen genetics
- Abstract
Human chromosome 21 is the smallest and one of the most intensively studied autosomes. The generation of high quality genetic and physical maps for the long arm has enabled the research community to accelerate gene discovery and the identification of disease loci on the chromosome. However, the emerging pattern from large-scale transcriptional mapping from many groups suggests that the majority of the 600-1000 genes predicted to reside on the chromosome are clustered in two distinct regions of the long arm, on distal 21q22.1 and 21q22.3. Here, we report the mapping of the gene for receptor interacting protein 140 (RIP140) on 21q11 by means of YACs, PACs and hybrid cell lines. We have placed RIP140 within 100 kb of D21S13, in a region of the chromosome where only one other gene has been described to date. The association of the RIP140 protein with the superfamily of nuclear receptors may be of significance in studies of trisomy 21 (Down syndrome) and Alzheimers disease, since a modifier locus has been speculated to reside on 21q11.
- Published
- 1998
- Full Text
- View/download PDF
34. An integrated map with cosmid/PAC contigs of a 4-Mb Down syndrome critical region.
- Author
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Osoegawa K, Susukida R, Okano S, Kudoh J, Minoshima S, Shimizu N, de Jong PJ, Groet J, Ives J, Lehrach H, Nizetic D, and Soeda E
- Subjects
- Bacteriophage P1 genetics, Chromosome Walking, Cloning, Molecular, Cosmids genetics, Exons genetics, Genetic Vectors genetics, Humans, Male, Restriction Mapping, Chromosome Mapping methods, Chromosomes, Human, Pair 21, Down Syndrome genetics, Gene Library
- Abstract
The major phenotypic features of Down syndrome have been correlated with partial trisomies of chromosome 21, allowing us to define the candidate gene region to a 4-Mb segment on the 21q22.2 band. We present here a high-resolution physical map with megabase-sized cosmid/PAC contigs. This ordered clone library has provided unique material for the integration of a variety of mappable objects, including exons, cDNAs, restriction sites, etc. Furthermore, our results have exemplified a strategy for the completion of the chromosome 21 map to sequencing.
- Published
- 1996
- Full Text
- View/download PDF
35. Non-recombinant background in gene targeting: illegitimate recombination between a hpt gene and a defective 5' deleted nptII gene can restore a Kmr phenotype in tobacco.
- Author
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de Groot MJ, Offringa R, Groet J, Does MP, Hooykaas PJ, and van den Elzen PJ
- Subjects
- Amino Acid Sequence, Base Sequence, Blotting, Southern, Cloning, Molecular, DNA isolation & purification, DNA metabolism, DNA Primers, DNA, Bacterial metabolism, Electroporation, Kanamycin Kinase, Molecular Sequence Data, Phenotype, Phosphotransferases (Alcohol Group Acceptor) biosynthesis, Plants, Genetically Modified, Plasmids, Polymerase Chain Reaction methods, Recombination, Genetic, Sequence Deletion, Phosphotransferases (Alcohol Group Acceptor) genetics, Plants, Toxic, Nicotiana genetics
- Abstract
Previously we have demonstrated gene targeting in plants after Agrobacterium-mediated transformation. In these initial experiments a transgenic tobacco line 104 containing a T-DNA insertion with a defective neomycin phosphotransferase (nptII) gene was transformed with a repair construct containing an otherwise defective nptII gene. Homologous recombination between the chromosomally located target and the incoming complementary defective nptII construct generated an intact nptII gene and led to a kanamycin-resistant (Kmr) phenotype. The gene targeting frequency was 1 x 10(-5). In order to compare direct gene transfer and Agrobacterium-mediated transformation with respect to gene targeting we transformed the same transgenic tobacco line 104 via electroporation. A total of 1.35 x 10(8) protoplasts were transformed with the repair construct. Out of nearly 221,000 transformed cells 477 Kmr calli were selected. Screening the Kmr calli via PCR for recombination events revealed that in none of these calli gene targeting had occurred. To establish the origin of the high number of Kmr calli in which gene targeting had not occurred we analysed plants regenerated from 24 Kmr calli via PCR and sequence analysis. This revealed that in 21 out of 24 plants analysed the 5'-deleted nptII gene was fused to the hygromycin phosphotransferase (hpt) gene that was also present on the repair construct. Sequence analysis of 7 hpt/nptII gene fusions showed that they all contained a continuous open reading frame. The absence of significant homology at the fusion site indicated that fusion occurred via a process of illegitimate recombination. Therefore, illegitimate recombination between an introduced defective gene and another gene present on the repair construct or the chromosome has to be taken into account as a standard byproduct in gene targeting experiments.
- Published
- 1994
- Full Text
- View/download PDF
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