248 results on '"DeJesus-Hernandez, Mariely"'
Search Results
2. Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
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Pottier, Cyril, Ren, Yingxue, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, van Rooij, Jeroen GJ, Murray, Melissa E, Christopher, Elizabeth, McDonnell, Shannon K, Fogarty, Zachary, Batzler, Anthony, Tian, Shulan, Vicente, Cristina T, Matchett, Billie, Karydas, Anna M, Hsiung, Ging-Yuek Robin, Seelaar, Harro, Mol, Merel O, Finger, Elizabeth C, Graff, Caroline, Öijerstedt, Linn, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Prudlo, Johannes, Rizzu, Patrizia, Simon-Sanchez, Javier, Edbauer, Dieter, Roeber, Sigrun, Diehl-Schmid, Janine, Evers, Bret M, King, Andrew, Mesulam, M Marsel, Weintraub, Sandra, Geula, Changiz, Bieniek, Kevin F, Petrucelli, Leonard, Ahern, Geoffrey L, Reiman, Eric M, Woodruff, Bryan K, Caselli, Richard J, Huey, Edward D, Farlow, Martin R, Grafman, Jordan, Mead, Simon, Grinberg, Lea T, Spina, Salvatore, Grossman, Murray, Irwin, David J, Lee, Edward B, Suh, EunRan, Snowden, Julie, Mann, David, Ertekin-Taner, Nilufer, Uitti, Ryan J, Wszolek, Zbigniew K, Josephs, Keith A, Parisi, Joseph E, Knopman, David S, Petersen, Ronald C, Hodges, John R, Piguet, Olivier, Geier, Ethan G, Yokoyama, Jennifer S, Rissman, Robert A, Rogaeva, Ekaterina, Keith, Julia, Zinman, Lorne, Tartaglia, Maria Carmela, Cairns, Nigel J, Cruchaga, Carlos, Ghetti, Bernardino, Kofler, Julia, Lopez, Oscar L, Beach, Thomas G, Arzberger, Thomas, Herms, Jochen, Honig, Lawrence S, Vonsattel, Jean Paul, Halliday, Glenda M, Kwok, John B, White, Charles L, Gearing, Marla, Glass, Jonathan, Rollinson, Sara, Pickering-Brown, Stuart, Rohrer, Jonathan D, Trojanowski, John Q, Van Deerlin, Vivianna, Bigio, Eileen H, Troakes, Claire, Al-Sarraj, Safa, Asmann, Yan, Miller, Bruce L, Graff-Radford, Neill R, Boeve, Bradley F, and Seeley, William W
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Biomedical and Clinical Sciences ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Clinical Research ,Brain Disorders ,Rare Diseases ,Human Genome ,Alzheimer's Disease Related Dementias (ADRD) ,Dementia ,Prevention ,Genetics ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Acquired Cognitive Impairment ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Aged ,DNA Repeat Expansion ,Dipeptidyl-Peptidases and Tripeptidyl-Peptidases ,Female ,Frontal Lobe ,Frontotemporal Lobar Degeneration ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,HLA-DQ Antigens ,Humans ,Intracellular Signaling Peptides and Proteins ,Loss of Function Mutation ,Male ,Middle Aged ,Nerve Tissue Proteins ,Potassium Channels ,Progranulins ,Protein Serine-Threonine Kinases ,Proteins ,RNA ,Messenger ,Risk Factors ,Sequence Analysis ,RNA ,Societies ,Scientific ,TDP-43 Proteinopathies ,White People ,Whole-genome sequencing FTLD-TDP ,TBK1 ,DPP6 ,UNC13A ,HLA ,Immunity ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
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- 2019
3. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study
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Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, de Munain, Adolfo López, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, NiCole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, EunRan, Lopez, Oscar L, Wong, Tsz H, van Rooij, Jeroen GJ, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Sabbagh, Marwan Noel, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-Paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, and Pickering-Brown, Stuart
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Dementia ,Genetics ,Aging ,Prevention ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Human Genome ,Alzheimer's Disease Related Dementias (ADRD) ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Age of Onset ,Aged ,Case-Control Studies ,Cerebellum ,Female ,Frontotemporal Lobar Degeneration ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Glial Cell Line-Derived Neurotrophic Factor Receptors ,Humans ,Male ,Middle Aged ,Mutation ,Progranulins ,RNA ,Messenger ,Neurology & Neurosurgery ,Clinical sciences - Abstract
BackgroundLoss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.MethodsThe study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p
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- 2018
4. Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72
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van Blitterswijk, Marka, Gendron, Tania F, Baker, Matthew C, DeJesus-Hernandez, Mariely, Finch, NiCole A, Brown, Patricia H, Daughrity, Lillian M, Murray, Melissa E, Heckman, Michael G, Jiang, Jie, Lagier-Tourenne, Clotilde, Edbauer, Dieter, Cleveland, Don W, Josephs, Keith A, Parisi, Joseph E, Knopman, David S, Petersen, Ronald C, Petrucelli, Leonard, Boeve, Bradley F, Graff-Radford, Neill R, Boylan, Kevin B, Dickson, Dennis W, and Rademakers, Rosa
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Biomedical and Clinical Sciences ,Neurosciences ,Brain Disorders ,Acquired Cognitive Impairment ,Dementia ,Genetics ,Aged ,Aged ,80 and over ,Amyotrophic Lateral Sclerosis ,C9orf72 Protein ,Cerebellum ,DNA Repeat Expansion ,Female ,Frontal Lobe ,Frontotemporal Dementia ,Genetic Association Studies ,Genetic Variation ,Heterozygote ,Humans ,Introns ,Male ,Middle Aged ,Motor Neuron Disease ,Promoter Regions ,Genetic ,Proteins ,Survival Analysis ,Tissue Banks ,C9ORF72 ,Frontotemporal dementia ,Frontotemporal lobar degeneration ,Motor neuron disease ,Amyotrophic lateral sclerosis ,Disease modifier ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
The loss of chromosome 9 open reading frame 72 (C9ORF72) expression, associated with C9ORF72 repeat expansions, has not been examined systematically. Three C9ORF72 transcript variants have been described thus far; the GGGGCC repeat is located between two non-coding exons (exon 1a and exon 1b) in the promoter region of transcript variant 2 (NM_018325.4) or in the first intron of variant 1 (NM_145005.6) and variant 3 (NM_001256054.2). We studied C9ORF72 expression in expansion carriers (n = 56) for whom cerebellum and/or frontal cortex was available. Using quantitative real-time PCR and digital molecular barcoding techniques, we assessed total C9ORF72 transcripts, variant 1, variant 2, variant 3, and intron containing transcripts [upstream of the expansion (intron 1a) and downstream of the expansion (intron 1b)]; the latter were correlated with levels of poly(GP) and poly(GA) proteins aberrantly translated from the expansion as measured by immunoassay (n = 50). We detected a decrease in expansion carriers as compared to controls for total C9ORF72 transcripts, variant 1, and variant 2: the strongest association was observed for variant 2 (quantitative real-time PCR cerebellum: median 43 %, p = 1.26e-06, and frontal cortex: median 58 %, p = 1.11e-05; digital molecular barcoding cerebellum: median 31 %, p = 5.23e-10, and frontal cortex: median 53 %, p = 5.07e-10). Importantly, we revealed that variant 1 levels greater than the 25th percentile conferred a survival advantage [digital molecular barcoding cerebellum: hazard ratio (HR) 0.31, p = 0.003, and frontal cortex: HR 0.23, p = 0.0001]. When focusing on intron containing transcripts, analysis of the frontal cortex revealed an increase of potentially truncated transcripts in expansion carriers as compared to controls [digital molecular barcoding frontal cortex (intron 1a): median 272 %, p = 0.003], with the highest levels in patients pathologically diagnosed with frontotemporal lobar degeneration. In the cerebellum, our analysis suggested that transcripts were less likely to be truncated and, excitingly, we discovered that intron containing transcripts were associated with poly(GP) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.33, p = 0.02, and (intron 1b): r = 0.49, p = 0.0004] and poly(GA) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.34, p = 0.02, and (intron 1b): r = 0.38, p = 0.007]. In summary, we report decreased expression of specific C9ORF72 transcripts and provide support for the presence of truncated transcripts as well as pre-mRNAs that may serve as templates for RAN translation. We further show that higher C9ORF72 levels may have beneficial effects, which warrants caution in the development of new therapeutic approaches.
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- 2015
5. Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers
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van Blitterswijk, Marka, Mullen, Bianca, Heckman, Michael G, Baker, Matthew C, DeJesus-Hernandez, Mariely, Brown, Patricia H, Murray, Melissa E, Hsiung, Ging-Yuek R, Stewart, Heather, Karydas, Anna M, Finger, Elizabeth, Kertesz, Andrew, Bigio, Eileen H, Weintraub, Sandra, Mesulam, Marsel, Hatanpaa, Kimmo J, White, Charles L, Neumann, Manuela, Strong, Michael J, Beach, Thomas G, Wszolek, Zbigniew K, Lippa, Carol, Caselli, Richard, Petrucelli, Leonard, Josephs, Keith A, Parisi, Joseph E, Knopman, David S, Petersen, Ronald C, Mackenzie, Ian R, Seeley, William W, Grinberg, Lea T, Miller, Bruce L, Boylan, Kevin B, Graff-Radford, Neill R, Boeve, Bradley F, Dickson, Dennis W, and Rademakers, Rosa
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Biomedical and Clinical Sciences ,Neurosciences ,Genetics ,ALS ,Neurodegenerative ,Acquired Cognitive Impairment ,Clinical Research ,Dementia ,Frontotemporal Dementia (FTD) ,Rare Diseases ,Aging ,Brain Disorders ,Neurological ,Adult ,Ataxins ,C9orf72 Protein ,Cohort Studies ,DNA Repeat Expansion ,Frontotemporal Dementia ,Genetic Association Studies ,Heterozygote ,Humans ,Male ,Membrane Proteins ,Middle Aged ,Motor Neuron Disease ,Nerve Tissue Proteins ,Proteins ,Survival of Motor Neuron 1 Protein ,Survival of Motor Neuron 2 Protein ,C9ORF72 ,Ataxin-2 ,ATXN2 ,Motor neuron disease ,Amyotrophic lateral sclerosis ,Frontotemporal dementia ,Disease modifier ,Clinical Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated 4 genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1), and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 control subjects, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1, or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% vs. 0% in control subjects, p = 0.013), whereas the frequency in probands with FTD was identical to control subjects. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.
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- 2014
6. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia
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van Blitterswijk, Marka, Mullen, Bianca, Nicholson, Alexandra M, Bieniek, Kevin F, Heckman, Michael G, Baker, Matthew C, DeJesus-Hernandez, Mariely, Finch, NiCole A, Brown, Patricia H, Murray, Melissa E, Hsiung, Ging-Yuek R, Stewart, Heather, Karydas, Anna M, Finger, Elizabeth, Kertesz, Andrew, Bigio, Eileen H, Weintraub, Sandra, Mesulam, Marsel, Hatanpaa, Kimmo J, White III, Charles L, Strong, Michael J, Beach, Thomas G, Wszolek, Zbigniew K, Lippa, Carol, Caselli, Richard, Petrucelli, Leonard, Josephs, Keith A, Parisi, Joseph E, Knopman, David S, Petersen, Ronald C, Mackenzie, Ian R, Seeley, William W, Grinberg, Lea T, Miller, Bruce L, Boylan, Kevin B, Graff-Radford, Neill R, Boeve, Bradley F, Dickson, Dennis W, and Rademakers, Rosa
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Biomedical and Clinical Sciences ,Neurosciences ,Dementia ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Alzheimer's Disease Related Dementias (ADRD) ,Genetics ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,ALS ,Human Genome ,Clinical Research ,Rare Diseases ,Acquired Cognitive Impairment ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Age of Onset ,Aged ,Aged ,80 and over ,Alleles ,C9orf72 Protein ,Cohort Studies ,DNA Repeat Expansion ,DNA-Binding Proteins ,Female ,Frontotemporal Dementia ,Genetic Predisposition to Disease ,Genotype ,Heterozygote ,Humans ,Male ,Membrane Proteins ,Middle Aged ,Models ,Genetic ,Motor Neuron Disease ,Nerve Tissue Proteins ,Polymorphism ,Single Nucleotide ,Proteins ,C9ORF72 ,TMEM106B ,Frontotemporal dementia ,Motor neuron disease ,Amyotrophic lateral sclerosis ,Disease modifier ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.
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- 2014
7. C9ORF72 repeat expansions in cases with previously identified pathogenic mutations
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van Blitterswijk, Marka, Baker, Matthew C, DeJesus-Hernandez, Mariely, Ghidoni, Roberta, Benussi, Luisa, Finger, Elizabeth, Hsiung, Ging-Yuek R, Kelley, Brendan J, Murray, Melissa E, Rutherford, Nicola J, Brown, Patricia E, Ravenscroft, Thomas, Mullen, Bianca, Ash, Peter EA, Bieniek, Kevin F, Hatanpaa, Kimmo J, Karydas, Anna, Wood, Elisabeth McCarty, Coppola, Giovanni, Bigio, Eileen H, Lippa, Carol, Strong, Michael J, Beach, Thomas G, Knopman, David S, Huey, Edward D, Mesulam, Marsel, Bird, Thomas, White, Charles L, Kertesz, Andrew, Geschwind, Dan H, Van Deerlin, Vivianna M, Petersen, Ronald C, Binetti, Giuliano, Miller, Bruce L, Petrucelli, Leonard, Wszolek, Zbigniew K, Boylan, Kevin B, Graff-Radford, Neill R, Mackenzie, Ian R, Boeve, Bradley F, Dickson, Dennis W, and Rademakers, Rosa
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Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Frontotemporal Dementia (FTD) ,Dementia ,Brain Disorders ,Clinical Research ,Neurosciences ,Alzheimer's Disease Related Dementias (ADRD) ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Aged ,Aged ,80 and over ,Autopsy ,C9orf72 Protein ,Cohort Studies ,DNA Repeat Expansion ,Female ,Follow-Up Studies ,Genetic Predisposition to Disease ,Genetic Testing ,Humans ,Intercellular Signaling Peptides and Proteins ,Male ,Microtubule-Associated Proteins ,Middle Aged ,Neurodegenerative Diseases ,Phenotype ,Progranulins ,Proteins ,tau Proteins ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.MethodsA 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.ResultsWe detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.ConclusionsOur findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
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- 2013
8. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype
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Rutherford, Nicola J, Heckman, Michael G, DeJesus-Hernandez, Mariely, Baker, Matt C, Soto-Ortolaza, Alexandra I, Rayaprolu, Sruti, Stewart, Heather, Finger, Elizabeth, Volkening, Kathryn, Seeley, William W, Hatanpaa, Kimmo J, Lomen-Hoerth, Catherine, Kertesz, Andrew, Bigio, Eileen H, Lippa, Carol, Knopman, David S, Kretzschmar, Hans A, Neumann, Manuela, Caselli, Richard J, White, Charles L, Mackenzie, Ian R, Petersen, Ronald C, Strong, Michael J, Miller, Bruce L, Boeve, Bradley F, Uitti, Ryan J, Boylan, Kevin B, Wszolek, Zbigniew K, Graff-Radford, Neill R, Dickson, Dennis W, Ross, Owen A, and Rademakers, Rosa
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Biomedical and Clinical Sciences ,Neurosciences ,Acquired Cognitive Impairment ,ALS ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Rare Diseases ,Brain Disorders ,Genetics ,Dementia ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease Related Dementias (ADRD) ,Neurodegenerative ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Aged ,Aged ,80 and over ,Amyotrophic Lateral Sclerosis ,C9orf72 Protein ,DNA Repeat Expansion ,Female ,Frontotemporal Dementia ,Genetic Predisposition to Disease ,Humans ,Male ,Middle Aged ,Proteins ,Amyotrophic lateral sclerosis ,Frontotemporal dementia ,C9ORF72 ,Repeat-expansion disease ,Association study ,Clinical Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Expansions of the noncoding GGGGCC hexanucleotide repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study we aimed to determine whether the length of the normal-unexpanded-allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS, and 160 FTD-ALS patients, and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or nonmutation carriers.
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- 2012
9. Frontotemporal dementia due to C9ORF72 mutations
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Sha, Sharon J, Takada, Leonel T, Rankin, Katherine P, Yokoyama, Jennifer S, Rutherford, Nicola J, Fong, Jamie C, Khan, Baber, Karydas, Anna, Baker, Matt C, DeJesus-Hernandez, Mariely, Pribadi, Mochtar, Coppola, Giovanni, Geschwind, Daniel H, Rademakers, Rosa, Lee, Suzee E, Seeley, William, Miller, Bruce L, and Boxer, Adam L
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Aging ,Frontotemporal Dementia (FTD) ,Dementia ,Brain Disorders ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease Related Dementias (ADRD) ,Neurodegenerative ,Alzheimer's Disease ,ALS ,Rare Diseases ,Acquired Cognitive Impairment ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adult ,Age of Onset ,Aged ,Amyotrophic Lateral Sclerosis ,Atrophy ,Brain ,C9orf72 Protein ,DNA Repeat Expansion ,Female ,Frontotemporal Dementia ,Humans ,Male ,Middle Aged ,Mutation ,Neuroimaging ,Neuropsychological Tests ,Proteins ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo describe the phenotype of patients with C9FTD/ALS (C9ORF72) hexanucleotide repeat expansion.MethodsA total of 648 patients with frontotemporal dementia (FTD)-related clinical diagnoses and Alzheimer disease (AD) dementia were tested for C9ORF72 expansion and 31 carried expanded repeats (C9+). Clinical and neuroimaging data were compared between C9+ (15 behavioral variant FTD [bvFTD], 11 FTD-motor neuron disease [MND], 5 amyotrophic lateral sclerosis [ALS]) and sporadic noncarriers (48 bvFTD, 19 FTD-MND, 6 ALS).ResultsAll C9+ patients displayed clinical syndromes of bvFTD, ALS, or FTD-MND. At first evaluation, C9+ bvFTD patients had more delusions and greater impairment of working memory, but milder eating dysregulation compared to bvFTD noncarriers. C9+FTD-MND patients had a trend for longer survival and had an earlier age at onset than FTD-MND noncarriers. Voxel-based morphometry demonstrated more thalamic atrophy in FTD and FTD-MND carriers than in noncarriers.ConclusionsPatients with the C9ORF72 hexanucleotide repeat expansion develop bvFTD, ALS, or FTD-MND with similar clinical and imaging features to sporadic cases. Other FTD spectrum diagnoses and AD dementia appear rare or absent among C9+ individuals. Longer survival in C9+ FTD-MND suggests slower disease progression and thalamic atrophy represents a novel and unexpected feature.
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- 2012
10. Frontotemporal Dementia in a Brazilian Kindred With the C9orf72 Mutation
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Takada, Leonel T, Pimentel, Maria Lucia V, DeJesus-Hernandez, Mariely, Fong, Jamie C, Yokoyama, Jennifer S, Karydas, Anna, Thibodeau, Marie-Pierre, Rutherford, Nicola J, Baker, Matthew C, Lomen-Hoerth, Catherine, Rademakers, Rosa, and Miller, Bruce L
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Neurodegenerative ,Clinical Research ,Genetics ,Dementia ,Rare Diseases ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Frontotemporal Dementia (FTD) ,ALS ,Alzheimer's Disease Related Dementias (ADRD) ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Age of Onset ,Aged ,Amyotrophic Lateral Sclerosis ,Atrophy ,Brain ,Brazil ,C9orf72 Protein ,DNA Repeat Expansion ,Family ,Female ,Frontotemporal Dementia ,Humans ,Male ,Middle Aged ,Mutation ,Neuroimaging ,Pedigree ,Personality ,Phenotype ,Proteins - Abstract
ObjectivesTo describe the clinical features of a Brazilian kindred with C9orf72 frontotemporal dementia-amyotrophic lateral sclerosis and compare them with other described families with C9orf72 and frontotemporal dementia-amyotrophic lateral sclerosis-causing mutations.DesignReport of a kindred.SettingDementia center at a university hospital.PatientsOne kindred encompassing 3 generations.ResultsThe presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed polymerase chain reaction and Southern blot. The observed phenotypes were behavioral variant frontotemporal dementia and amyotrophic lateral sclerosis with dementia, with significant variability in age at onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations, and more posterior atrophy on neuroimaging than is typical for frontotemporal dementia were seen.ConclusionsBehavioral variant frontotemporal dementia due to C9orf72 expansion displays some phenotypic heterogeneity and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede the diagnosis of dementia by many years and may be a distinguishing feature of this mutation.
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- 2012
11. Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers
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Jackson, Jazmyne L., Finch, NiCole A., Baker, Matthew C., Kachergus, Jennifer M., DeJesus-Hernandez, Mariely, Pereira, Kimberly, Christopher, Elizabeth, Prudencio, Mercedes, Heckman, Michael G., Thompson, E. Aubrey, Dickson, Dennis W., Shah, Jaimin, Oskarsson, Björn, Petrucelli, Leonard, Rademakers, Rosa, and van Blitterswijk, Marka
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- 2020
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12. Extensive transcriptomic study emphasizes importance of vesicular transport in C9orf72 expansion carriers
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Dickson, Dennis W., Baker, Matthew C., Jackson, Jazmyne L., DeJesus-Hernandez, Mariely, Finch, NiCole A., Tian, Shulan, Heckman, Michael G., Pottier, Cyril, Gendron, Tania F., Murray, Melissa E., Ren, Yingxue, Reddy, Joseph S., Graff-Radford, Neill R., Boeve, Bradley F., Petersen, Ronald C., Knopman, David S., Josephs, Keith A., Petrucelli, Leonard, Oskarsson, Björn, Sheppard, John W., Asmann, Yan W., Rademakers, Rosa, and van Blitterswijk, Marka
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- 2019
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13. In-depth clinico-pathological examination of RNA foci in a large cohort of C9ORF72 expansion carriers
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DeJesus-Hernandez, Mariely, Finch, NiCole A., Wang, Xue, Gendron, Tania F., Bieniek, Kevin F., Heckman, Michael G., Vasilevich, Aliaksei, Murray, Melissa E., Rousseau, Linda, Weesner, Rachael, Lucido, Anthony, Parsons, Meeia, Chew, Jeannie, Josephs, Keith A., Parisi, Joseph E., Knopman, David S., Petersen, Ronald C., Boeve, Bradley F., Graff-Radford, Neill R., de Boer, Jan, Asmann, Yan W., Petrucelli, Leonard, Boylan, Kevin B., Dickson, Dennis W., van Blitterswijk, Marka, and Rademakers, Rosa
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- 2017
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14. Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins
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Gao, Junli, primary, Mewborne, Quinlan T., additional, Girdhar, Amandeep, additional, Sheth, Udit, additional, Coyne, Alyssa N., additional, Punathil, Ritika, additional, Kang, Bong Gu, additional, Dasovich, Morgan, additional, Veire, Austin, additional, DeJesus Hernandez, Mariely, additional, Liu, Shuaichen, additional, Shi, Zheng, additional, Dafinca, Ruxandra, additional, Fouquerel, Elise, additional, Talbot, Kevin, additional, Kam, Tae-In, additional, Zhang, Yong-Jie, additional, Dickson, Dennis, additional, Petrucelli, Leonard, additional, van Blitterswijk, Marka, additional, Guo, Lin, additional, Dawson, Ted M., additional, Dawson, Valina L., additional, Leung, Anthony K. L., additional, Lloyd, Thomas E., additional, Gendron, Tania F., additional, Rothstein, Jeffrey D., additional, and Zhang, Ke, additional
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- 2022
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15. Long-read sequencing across the C9orf72 ‘GGGGCC’ repeat expansion: implications for clinical use and genetic discovery efforts in human disease
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Ebbert, Mark T. W., Farrugia, Stefan L., Sens, Jonathon P., Jansen-West, Karen, Gendron, Tania F., Prudencio, Mercedes, McLaughlin, Ian J., Bowman, Brett, Seetin, Matthew, DeJesus-Hernandez, Mariely, Jackson, Jazmyne, Brown, Patricia H., Dickson, Dennis W., van Blitterswijk, Marka, Rademakers, Rosa, Petrucelli, Leonard, and Fryer, John D.
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- 2018
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16. Loss of Tmem106b is unable to ameliorate frontotemporal dementia-like phenotypes in an AAV mouse model of C9ORF72-repeat induced toxicity
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Nicholson, Alexandra M., Zhou, Xiaolai, Perkerson, Ralph B., Parsons, Tammee M., Chew, Jeannie, Brooks, Mieu, DeJesus-Hernandez, Mariely, Finch, NiCole A., Matchett, Billie J., Kurti, Aishe, Jansen-West, Karen R., Perkerson, Emilie, Daughrity, Lillian, Castanedes-Casey, Monica, Rousseau, Linda, Phillips, Virginia, Hu, Fenghua, Gendron, Tania F., Murray, Melissa E., Dickson, Dennis W., Fryer, John D., Petrucelli, Leonard, and Rademakers, Rosa
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- 2018
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17. Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study
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van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Niemantsverdriet, Ellis, Murray, Melissa E, Heckman, Michael G, Diehl, Nancy N, Brown, Patricia H, Baker, Matthew C, Finch, NiCole A, Bauer, Peter O, Serrano, Geidy, Beach, Thomas G, Josephs, Keith A, Knopman, David S, Petersen, Ronald C, Boeve, Bradley F, Graff-Radford, Neill R, Boylan, Kevin B, Petrucelli, Leonard, Dickson, Dennis W, and Rademakers, Rosa
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- 2013
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18. Analysis of the C9orf72 repeat in Parkinson's disease, essential tremor and restless legs syndrome
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DeJesus-Hernandez, Mariely, Rayaprolu, Sruti, Soto-Ortolaza, Alexandra I., Rutherford, Nicola J., Heckman, Michael G., Traynor, Sharleen, Strongosky, Audrey, Graff-Radford, Neill, Van Gerpen, Jay, Uitti, Ryan J., Shih, Jerry J., Lin, Siong-Chi, Wszolek, Zbigniew K., Rademakers, Rosa, and Ross, Owen A.
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- 2013
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19. A yeast functional screen predicts new candidate ALS disease genes
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Couthouis, Julien, Hart, Michael P., Shorter, James, DeJesus-Hernandez, Mariely, Erion, Renske, Oristano, Rachel, Liu, Annie X., Ramos, Daniel, Jethava, Niti, Hosangadi, Divya, Epstein, James, Chiang, Ashley, Diaz, Zamia, Nakaya, Tadashi, Ibrahim, Fadia, Kim, Hyung-Jun, Solski, Jennifer A., Williams, Kelly L., Mojsilovic-Petrovic, Jelena, Ingre, Caroline, Boylan, Kevin, Graff-Radford, Neill R., W. Dickson, Dennis, Clay-Falcone, Dana, Elman, Lauren, McCluskey, Leo, Greene, Robert, Kalb, Robert G., Lee, Virginia M.-Y., Trojanowski, John Q., Ludolph, Albert, Robberecht, Wim, Andersen, Peter M., Nicholson, Garth A., Blair, Ian P., King, Oliver D., Bonini, Nancy M., Van Deerlin, Vivianna, Rademakers, Rosa, Mourelatos, Zissimos, and Gitler, Aaron D.
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- 2011
20. Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations
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Pottier, Cyril, primary, Mateiu, Ligia, additional, Baker, Matthew C, additional, DeJesus-Hernandez, Mariely, additional, Teixeira Vicente, Cristina, additional, Finch, NiCole A, additional, Tian, Shulan, additional, van Blitterswijk, Marka, additional, Murray, Melissa E, additional, Ren, Yingxue, additional, Petrucelli, Leonard, additional, Oskarsson, Björn, additional, Biernacka, Joanna M, additional, Graff-Radford, Neill R, additional, Boeve, Bradley F, additional, Petersen, Ronald C, additional, Josephs, Keith A, additional, Asmann, Yan W, additional, Dickson, Dennis W, additional, and Rademakers, Rosa, additional
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- 2021
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21. Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72
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Murray, Melissa E., Bieniek, Kevin F., Banks Greenberg, M., DeJesus-Hernandez, Mariely, Rutherford, Nicola J., van Blitterswijk, Marka, Niemantsverdriet, Ellis, Ash, Peter E., Gendron, Tania F., Kouri, Naomi, Baker, Matt, Goodman, Ira J., Petrucelli, Leonard, Rademakers, Rosa, and Dickson, Dennis W.
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- 2013
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22. Single-cell profiling of the human primary motor cortex in ALS and FTLD
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Pineda, S. Sebastian, primary, Lee, Hyeseung, additional, Fitzwalter, Brent E., additional, Mohammadi, Shahin, additional, Pregent, Luc J., additional, Gardashli, Mahammad E., additional, Mantero, Julio, additional, Engelberg-Cook, Erica, additional, DeJesus-Hernandez, Mariely, additional, van Blitterswijk, Marka, additional, Pottier, Cyril, additional, Rademakers, Rosa, additional, Oskarsson, Bjorn, additional, Shah, Jaimin S., additional, Petersen, Ronald C., additional, Graff-Radford, Neill R., additional, Boeve, Bradley F., additional, Knopman, David S., additional, Josephs, Keith A., additional, DeTure, Michael, additional, Murray, Melissa E., additional, Dickson, Dennis W., additional, Heiman, Myriam, additional, Belzil, Veronique V., additional, and Kellis, Manolis, additional
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- 2021
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23. Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations.
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Pottier, Cyril, Mateiu, Ligia, Baker, Matthew C, DeJesus-Hernandez, Mariely, Vicente, Cristina Teixeira, Finch, NiCole A, Tian, Shulan, Blitterswijk, Marka van, Murray, Melissa E, Ren, Yingxue, Petrucelli, Leonard, Oskarsson, Björn, Biernacka, Joanna M, Graff-Radford, Neill R, Boeve, Bradley F, Petersen, Ronald C, Josephs, Keith A, Asmann, Yan W, Dickson, Dennis W, and Rademakers, Rosa
- Abstract
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A. [ABSTRACT FROM AUTHOR]
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- 2022
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24. Tau pathology in frontotemporal lobar degeneration with C9ORF72 hexanucleotide repeat expansion
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Bieniek, Kevin F., Murray, Melissa E., Rutherford, Nicola J., Castanedes-Casey, Monica, DeJesus-Hernandez, Mariely, Liesinger, Amanda M., Baker, Matthew C., Boylan, Kevin B., Rademakers, Rosa, and Dickson, Dennis W.
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- 2013
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25. Long-read targeted sequencing uncovers clinicopathological associations for C9orf72-linked diseases
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DeJesus-Hernandez, Mariely, primary, Aleff, Ross A, additional, Jackson, Jazmyne L, additional, Finch, NiCole A, additional, Baker, Matthew C, additional, Gendron, Tania F, additional, Murray, Melissa E, additional, McLaughlin, Ian J, additional, Harting, John R, additional, Graff-Radford, Neill R, additional, Oskarsson, Björn, additional, Knopman, David S, additional, Josephs, Keith A, additional, Boeve, Bradley F, additional, Petersen, Ronald C, additional, Fryer, John D, additional, Petrucelli, Leonard, additional, Dickson, Dennis W, additional, Rademakers, Rosa, additional, Ebbert, Mark T W, additional, Wieben, Eric D, additional, and van Blitterswijk, Marka, additional
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- 2021
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26. Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p
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Stewart, Heather, Rutherford, Nicola J., Briemberg, Hannah, Krieger, Charles, Cashman, Neil, Fabros, Marife, Baker, Matt, Fok, Alice, DeJesus-Hernandez, Mariely, Eisen, Andrew, Rademakers, Rosa, and Mackenzie, Ian R. A.
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- 2012
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27. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72
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Murray, Melissa E., DeJesus-Hernandez, Mariely, Rutherford, Nicola J., Baker, Matt, Duara, Ranjan, Graff-Radford, Neill R., Wszolek, Zbigniew K., Ferman, Tanis J., Josephs, Keith A., Boylan, Kevin B., Rademakers, Rosa, and Dickson, Dennis W.
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- 2011
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28. Genome-wide screen identifies rs646776 near sortilin as a regulator for progranulin levels in human plasma
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Carrasquillo, Minerva M., Nicholson, Alexandra M., Finch, NiCole, Gibbs, Raphael, Rutherford, Nicola J., Baker, Matt, Hunter, Talisha, DeJesus-Hernandez, Mariely, Bisceglio, Gina D., Mackenzie, Ian R., Singleton, Andrew, Cookson, Mark R., Crook, Julia E., Dillman, Allissa, Hernandez, Dena, Petersen, Ronald C., Graff-Radford, Neill R., Younkin, Steven G., and Rademakers, Rosa
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Proguanil -- Health aspects ,Neurogenesis -- Care and treatment ,Neurogenesis -- Genetic aspects ,Biological sciences - Abstract
A genome-wide association study of 313,504 DSNPs) in 533 control samples was performed to identify two SNPs with genome-wide significant association with plasma progranulin gene (GRN) levels on chromosome 1p13.3. The significant association of a locus identified on chromosome 1p13.3 with plasma GRN levels which implicated SNP rs646776 located near sortilin (SORT1) as an important regulator of GRN levels provides new pathways for future research into GRN biology and the pathophysiology of neurogenerative diseases.
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- 2010
29. A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories
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Akimoto, Chizuru, Volk, Alexander E, van Blitterswijk, Marka, Van den Broeck, Marleen, Leblond, Claire S, Lumbroso, Serge, Camu, William, Neitzel, Birgit, Onodera, Osamu, van Rheenen, Wouter, Pinto, Susana, Weber, Markus, Smith, Bradley, Proven, Melanie, Talbot, Kevin, Keagle, Pamela, Chesi, Alessandra, Ratti, Antonia, van der Zee, Julie, Alstermark, Helena, Birve, Anna, Calini, Daniela, Nordin, Angelica, Tradowsky, Daniela C, Just, Walter, Daoud, Hussein, Angerbauer, Sabrina, DeJesus-Hernandez, Mariely, Konno, Takuya, Lloyd-Jani, Anjali, de Carvalho, Mamede, Mouzat, Kevin, Landers, John E, Veldink, Jan H, Silani, Vincenzo, Gitler, Aaron D, Shaw, Christopher E, Rouleau, Guy A, van den Berg, Leonard H, Van Broeckhoven, Christine, Rademakers, Rosa, Andersen, Peter M, and Kubisch, Christian
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- 2014
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30. Characterization of a Family With c9FTD/ALS Associated With the GGGGCC Repeat Expansion in C9ORF72
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Savica, Rodolfo, Adeli, Anahita, Vemuri, Prashanthi, Knopman, David S., DeJesus-Hernandez, Mariely, Rademakers, Rosa, Fields, Julie A., Whitwell, Jennifer, Jack, Clifford R., Jr, Lowe, Val, Petersen, Ronald C., and Boeve, Bradley F.
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- 2012
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31. Frontotemporal Dementia in a Brazilian Kindred With the C9orf72 Mutation
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Takada, Leonel T., Pimentel, Maria Lucia, DeJesus-Hernandez, Mariely, Fong, Jamie C., Yokoyama, Jennifer S., Karydas, Anna, Thibodeau, Marie-Pierre, Rutherford, Nicola J., Baker, Matthew C., Lomen-Hoerth, Catherine, Rademakers, Rosa, and Miller, Bruce L.
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- 2012
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32. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p
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Hsiung, Ging-Yuek R., DeJesus-Hernandez, Mariely, Feldman, Howard H., Sengdy, Pheth, Bouchard-Kerr, Phoenix, Dwosh, Emily, Butler, Rachel, Leung, Bonnie, Fok, Alice, Rutherford, Nicola J., Baker, Matt, Rademakers, Rosa, and Mackenzie, Ian R. A.
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- 2012
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33. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics
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Whitwell, Jennifer L., Weigand, Stephen D., Boeve, Bradley F., Senjem, Matthew L., Gunter, Jeffrey L., DeJesus-Hernandez, Mariely, Rutherford, Nicola J., Baker, Matthew, Knopman, David S., Wszolek, Zbigniew K., Parisi, Joseph E., Dickson, Dennis W., Petersen, Ronald C., Rademakers, Rosa, Jack, Clifford R., Jr, and Josephs, Keith A.
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- 2012
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34. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72
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Boeve, Bradley F., Boylan, Kevin B., Graff-Radford, Neill R., DeJesus-Hernandez, Mariely, Knopman, David S., Pedraza, Otto, Vemuri, Prashanthi, Jones, David, Lowe, Val, Murray, Melissa E., Dickson, Dennis W., Josephs, Keith A., Rush, Beth K., Machulda, Mary M., Fields, Julie A., Ferman, Tanis J., Baker, Matthew, Rutherford, Nicola J., Adamson, Jennifer, Wszolek, Zbigniew K., Adeli, Anahita, Savica, Rodolfo, Boot, Brendon, Kuntz, Karen M., Gavrilova, Ralitza, Reeves, Andrew, Whitwell, Jennifer, Kantarci, Kejal, Jack, Clifford R., Jr, Parisi, Joseph E., Lucas, John A., Petersen, Ronald C., and Rademakers, Rosa
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- 2012
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35. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations
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Neumann, Manuela, Bentmann, Eva, Dormann, Dorothee, Jawaid, Ali, DeJesus-Hernandez, Mariely, Ansorge, Olaf, Roeber, Sigrun, Kretzschmar, Hans A., Munoz, David G., Kusaka, Hirofumi, Yokota, Osamu, Ang, Lee-Cyn, Bilbao, Juan, Rademakers, Rosa, Haass, Christian, and Mackenzie, Ian R. A.
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- 2011
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36. Ataxin-2 repeat-length variation and neurodegeneration
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Ross, Owen A., Rutherford, Nicola J., Baker, Matt, Soto-Ortolaza, Alexandra I., Carrasquillo, Minerva M., DeJesus-Hernandez, Mariely, Adamson, Jennifer, Li, Ma, Volkening, Kathryn, Finger, Elizabeth, Seeley, William W., Hatanpaa, Kimmo J., Lomen-Hoerth, Catherine, Kertesz, Andrew, Bigio, Eileen H., Lippa, Carol, Woodruff, Bryan K., Knopman, David S., White, Charles L., III, Van Gerpen, Jay A., Meschia, James F., Mackenzie, Ian R., Boylan, Kevin, Boeve, Bradley F., Miller, Bruce L., Strong, Michael J., Uitti, Ryan J., Younkin, Steven G., Graff-Radford, Neill R., Petersen, Ronald C., Wszolek, Zbigniew K., Dickson, Dennis W., and Rademakers, Rosa
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- 2011
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37. FUS GENE MUTATIONS IN FAMILIAL AND SPORADIC AMYOTROPHIC LATERAL SCLEROSIS
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RADEMAKERS, ROSA, STEWART, HEATHER, DEJESUS-HERNANDEZ, MARIELY, KRIEGER, CHARLES, GRAFF-RADFORD, NEILL, FABROS, MARIFE, BRIEMBERG, HANNAH, CASHMAN, NEIL, EISEN, ANDREW, and MACKENZIE, IAN R.A.
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- 2010
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38. De Novo Truncating FUS Gene Mutation as a Cause of Sporadic Amyotrophic Lateral Sclerosis
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DeJesus-Hernandez, Mariely, Kocerha, Jannet, Finch, NiCole, Crook, Richard, Baker, Matt, Desaro, Pamela, Johnston, Amelia, Rutherford, Nicola, Wojtas, Aleksandra, Kennelly, Kathleen, Wszolek, Zbigniew K., Graff-Radford, Neill, Boylan, Kevin, and Rademakers, Rosa
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- 2010
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39. Pathogenicity of exonic indels in fused in sarcoma in amyotrophic lateral sclerosis
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Rutherford, Nicola J., Finch, Nicole A., DeJesus-Hernandez, Mariely, Crook, Richard J.P., Lomen-Hoerth, Catherine, Wszolek, Zbigniew K., Uitti, Ryan J., Graff-Radford, Neill R., and Rademakers, Rosa
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- 2012
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40. The chromosome 9 ALS and FTD locus is probably derived from a single founder
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Mok, Kin, Traynor, Bryan J., Schymick, Jennifer, Tienari, Pentti J., Laaksovirta, Hannu, Peuralinna, Terhi, Myllykangas, Liisa, Chiò, Adriano, Shatunov, Aleksey, Boeve, Bradley F., Boxer, Adam L., DeJesus-Hernandez, Mariely, Mackenzie, Ian R., Waite, Adrian, Williams, Nigel, Morris, Huw R., Simón-Sánchez, Javier, van Swieten, John C., Heutink, Peter, Restagno, Gabriella, Mora, Gabriele, Morrison, Karen E., Shaw, Pamela J., Rollinson, Pamela Sara, Al-Chalabi, Ammar, Rademakers, Rosa, Pickering-Brown, Stuart, Orrell, Richard W., Nalls, Michael A., and Hardy, John
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- 2012
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41. Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis
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Verbeeck Christophe, Deng Qiudong, DeJesus-Hernandez Mariely, Taylor Georgia, Ceballos-Diaz Carolina, Kocerha Jannet, Golde Todd, Das Pritam, Rademakers Rosa, Dickson Dennis W, and Kukar Thomas
- Subjects
Amyotrophic lateral sclerosis ,Frontotemporal lobar degeneration ,Fused in sarcoma proteinopathies ,Transgenic mouse models ,Adeno-associated virus ,Neuronal cytoplasmic inclusions ,Ubiquitin ,p62/SQSTM1 ,α-internexin ,PABP-1 ,Stress granules ,RNA dysfunction ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Mutations in the gene encoding the RNA-binding protein fused in sarcoma (FUS) can cause familial and sporadic amyotrophic lateral sclerosis (ALS) and rarely frontotemproal dementia (FTD). FUS accumulates in neuronal cytoplasmic inclusions (NCIs) in ALS patients with FUS mutations. FUS is also a major pathologic marker for a group of less common forms of frontotemporal lobar degeneration (FTLD), which includes atypical FTLD with ubiquitinated inclusions (aFTLD-U), neuronal intermediate filament inclusion disease (NIFID) and basophilic inclusion body disease (BIBD). These diseases are now called FUS proteinopathies, because they share this disease marker. It is unknown how FUS mutations cause disease and the role of FUS in FTD-FUS cases, which do not have FUS mutations. In this paper we report the development of somatic brain transgenic (SBT) mice using recombinant adeno-associated virus (rAAV) to investigate how FUS mutations lead to neurodegeneration. Results We compared SBT mice expressing wild-type human FUS (FUSWT), and two ALS-linked mutations: FUSR521C and FUSΔ14, which lacks the nuclear localization signal. Both FUS mutants accumulated in the cytoplasm relative to FUSWT. The degree of this shift correlated with the severity of the FUS mutation as reflected by disease onset in humans. Mice expressing the most aggressive mutation, FUSΔ14, recapitulated many aspects of FUS proteinopathies, including insoluble FUS, basophilic and eosiniphilic NCIs, and other pathologic markers, including ubiquitin, p62/SQSTM1, α-internexin, and the poly-adenylate(A)-binding protein 1 (PABP-1). However, TDP-43 did not localize to inclusions. Conclusions Our data supports the hypothesis that ALS or FTD-linked FUS mutations cause neurodegeneration by increasing cyotplasmic FUS. Accumulation of FUS in the cytoplasm may retain RNA targets and recruit additional RNA-binding proteins, such as PABP-1, into stress-granule like aggregates that coalesce into permanent inclusions that could negatively affect RNA metabolism. Identification of mutations in other genes that cause ALS/FTD, such as C9ORF72, sentaxin, and angiogenin, lends support to the idea that defective RNA metabolism is a critical pathogenic pathway. The SBT FUS mice described here will provide a valuable platform for dissecting the pathogenic mechanism of FUS mutations, define the relationship between FTD and ALS-FUS, and help identify therapeutic targets that are desperately needed for these devastating neurodegenerative disorders.
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- 2012
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42. Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations
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Kocerha Jannet, Kouri Naomi, Baker Matt, Finch NiCole, DeJesus-Hernandez Mariely, Gonzalez John, Chidamparam Kumaravel, Josephs Keith A, Boeve Bradley F, Graff-Radford Neill R, Crook Julia, Dickson Dennis W, and Rademakers Rosa
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Frontotemporal lobar degeneration ,TDP-43 ,microRNA ,progranulin ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (PGRN) gene. Results Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying PGRN mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of PGRN mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology. Conclusions Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and provides new insight into potential future therapeutic options.
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- 2011
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43. Long-read sequencing across theC9orf72‘GGGGCC’ repeat expansion: implications for clinical use and genetic discovery efforts in human disease
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Ebbert, Mark T. W., primary, Farrugia, Stefan, additional, Sens, Jonathon, additional, Jansen-West, Karen, additional, Gendron, Tania F., additional, Prudencio, Mercedes, additional, McLaughlin, lan J., additional, Bowman, Brett, additional, Seetin, Matthew, additional, DeJesus-Hernandez, Mariely, additional, Jackson, Jazmyne, additional, Brown, Patricia H, additional, Dickson, Dennis W., additional, van Blitterswijk, Marka, additional, Rademakers, Rosa, additional, Petrucelli, Leonard, additional, and Fryer, John D., additional
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- 2018
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44. Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers
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Finch, NiCole A., primary, Wang, Xue, additional, Baker, Matthew C., additional, Heckman, Michael G., additional, Gendron, Tania F., additional, Bieniek, Kevin F., additional, Wuu, Joanne, additional, DeJesus-Hernandez, Mariely, additional, Brown, Patricia H., additional, Chew, Jeannie, additional, Jansen-West, Karen R., additional, Daughrity, Lillian M., additional, Nicholson, Alexandra M., additional, Murray, Melissa E., additional, Josephs, Keith A., additional, Parisi, Joseph E., additional, Knopman, David S., additional, Petersen, Ronald C., additional, Petrucelli, Leonard, additional, Boeve, Bradley F., additional, Graff-Radford, Neill R., additional, Asmann, Yan W., additional, Dickson, Dennis W., additional, Benatar, Michael, additional, Bowser, Robert, additional, Boylan, Kevin B., additional, Rademakers, Rosa, additional, and van Blitterswijk, Marka, additional
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- 2017
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45. Brain atrophy over time in genetic and sporadic frontotemporal dementia: a study on 198 serial MRI
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Whitwell, Jennifer L., Boeve, Bradley F., Weigand, Stephen D., Senjem, Matthew L., Gunter, Jeffrey L., Baker, Matthew C., DeJesus-Hernandez, Mariely, Knopman, David S., Wszolek, Zbigniew K., Petersen, Ronald C., Rademakers, Rosa, Jack, Clifford R., and Josephs, Keith A.
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Male ,C9orf72 Protein ,Brain ,Proteins ,tau Proteins ,Middle Aged ,Magnetic Resonance Imaging ,Article ,Progranulins ,Frontotemporal Dementia ,Mutation ,Humans ,Intercellular Signaling Peptides and Proteins ,Female ,Longitudinal Studies ,Atrophy ,Biomarkers ,Aged - Abstract
The aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule-associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD.In this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n = 21), GRN mutations (n = 11), C9ORF72 repeat expansions (n = 11) or sporadic FTD (n = 15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor-based morphometry. Sample size estimates were calculated.Progressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD.These data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.
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- 2015
46. Frontotemporal dementia in a Brazilian Caucasian kindred with the C9orf72 mutation
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Takada, Leonel T., Pimentel, Maria Lucia V., DeJesus-Hernandez, Mariely, Fong, Jamie C., Yokoyama, Jennifer S., Karydas, Anna, Thibodeau, Marie-Pierre, Rutherford, Nicola J., Baker, Matthew C., Lomen-Hoerth, Catherine, Rademakers, Rosa, and Miller, Bruce L.
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Adult ,Male ,DNA Repeat Expansion ,C9orf72 Protein ,Amyotrophic Lateral Sclerosis ,Brain ,Proteins ,Neuroimaging ,Middle Aged ,Article ,Pedigree ,Phenotype ,Frontotemporal Dementia ,Mutation ,Humans ,Family ,Female ,Age of Onset ,Atrophy ,Brazil ,Aged ,Personality - Abstract
To describe the clinical features of a Brazilian kindred with C9orf72 frontotemporal dementia-amyotrophic lateral sclerosis and compare them with other described families with C9orf72 and frontotemporal dementia-amyotrophic lateral sclerosis-causing mutations.Report of a kindred.Dementia center at a university hospital.One kindred encompassing 3 generations.The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed polymerase chain reaction and Southern blot. The observed phenotypes were behavioral variant frontotemporal dementia and amyotrophic lateral sclerosis with dementia, with significant variability in age at onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations, and more posterior atrophy on neuroimaging than is typical for frontotemporal dementia were seen.Behavioral variant frontotemporal dementia due to C9orf72 expansion displays some phenotypic heterogeneity and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede the diagnosis of dementia by many years and may be a distinguishing feature of this mutation.
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- 2012
47. Transthyretin as Potential Biomarker for C9ORF72 -related Diseases (I8-2A)
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Van Blitterswijk, Marka, primary, Finch, NiCole, additional, Baker, Matthew, additional, Wang, Xue, additional, Bieniek, Kevin, additional, Dejesus-Hernandez, Mariely, additional, Gendron, Tania, additional, Asmann, Yan, additional, Heckman, Michael, additional, Brown, Patricia, additional, Josephs, Keith, additional, Parisi, Joseph, additional, Knopman, David, additional, Petersen, Ronald, additional, Petrucelli, Leonard, additional, Boeve, Bradley, additional, Graff-Radford, Neill, additional, Boylan, Kevin, additional, Dickson, Dennis, additional, and Rademakers, Rosa, additional
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- 2015
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48. Transthyretin as Potential Biomarker for C9ORF72 -related Diseases (S33.001)
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Van Blitterswijk, Marka, primary, Finch, NiCole, additional, Baker, Matthew, additional, Wang, Xue, additional, Bieniek, Kevin, additional, Dejesus-Hernandez, Mariely, additional, Gendron, Tania, additional, Asmann, Yan, additional, Heckman, Michael, additional, Brown, Patricia, additional, Josephs, Keith, additional, Parisi, Joseph, additional, Knopman, David, additional, Petersen, Ronald, additional, Petrucelli, Leonard, additional, Boeve, Bradley, additional, Graff-Radford, Neill, additional, Boylan, Kevin, additional, Dickson, Dennis, additional, and Rademakers, Rosa, additional
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- 2015
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49. Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene
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van Blitterswijk, Marka, primary, Mullen, Bianca, additional, Wojtas, Aleksandra, additional, Heckman, Michael G, additional, Diehl, Nancy N, additional, Baker, Matthew C, additional, DeJesus-Hernandez, Mariely, additional, Brown, Patricia H, additional, Murray, Melissa E, additional, Hsiung, Ging-Yuek R, additional, Stewart, Heather, additional, Karydas, Anna M, additional, Finger, Elizabeth, additional, Kertesz, Andrew, additional, Bigio, Eileen H, additional, Weintraub, Sandra, additional, Mesulam, Marsel, additional, Hatanpaa, Kimmo J, additional, White, Charles L, additional, Neumann, Manuela, additional, Strong, Michael J, additional, Beach, Thomas G, additional, Wszolek, Zbigniew K, additional, Lippa, Carol, additional, Caselli, Richard, additional, Petrucelli, Leonard, additional, Josephs, Keith A, additional, Parisi, Joseph E, additional, Knopman, David S, additional, Petersen, Ronald C, additional, Mackenzie, Ian R, additional, Seeley, William W, additional, Grinberg, Lea T, additional, Miller, Bruce L, additional, Boylan, Kevin B, additional, Graff-Radford, Neill R, additional, Boeve, Bradley F, additional, Dickson, Dennis W, additional, and Rademakers, Rosa, additional
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- 2014
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50. O3-03-05: LONGITUDINAL MRI AND NEUROPSYCHOLOGICAL CHANGES IN SYMPTOMATIC FRONTOTEMPORAL LOBAR DEGENERATION SUBJECTS WITH MUTATIONS IN MAPT, PGRN, AND C9ORF72
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Graff-Radford, Jonathan, primary, Jones, David, additional, Weigand, Stephen, additional, Przybelski, Scott, additional, Whitwell, Jennifer Louise, additional, Senjem, Mathew, additional, Knopman, David S., additional, Graff-Radford, Neill R., additional, Josephs, Keith, additional, Wszolek, Zbigniew, additional, Vemuri, Prashanthi, additional, Fields, Julie A., additional, Ferman, Tanis J., additional, Lucas, John, additional, Lowe, Val J., additional, Gavrilova, Ralitza, additional, Kuntz, Karen, additional, DeJesus Hernandez, Mariely, additional, Baker, Matthew, additional, Rademakers, Rosa, additional, Petersen, Ronald Carl, additional, Kantarci, Kejal, additional, Jack, Clifford, additional, and Boeve, Bradley F., additional
- Published
- 2014
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