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Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement
Open accessAbstract
OBJECTIVE: To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. DESIGN: Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. SETTING: Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. PATIENTS Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. MAIN OUTCOME MEASURE: Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). RESULTS: In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. CONCLUSIONS: Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.
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“In particular, there is converging evidence for the role of neuroinflammation in neurodegenerative dementias, including FTD, from genetic associations (Guerreiro et al., 2013; Rayaprolu et al., 2013; Broce et al., 2018), CSF (Sjogren et al., 2004; Woollacott et al., 2018), epidemiology (Miller et al., 2013, 2016), post-mortem tissue (Venneti et al., 2008; Lant et al., 2014) and animal models”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Guerreiro et al., 2013
In the citing paper
“Nonsense or missense mutations in TREM2 have been identified in several families with FTD.343–345”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [344]
In the citing paper
“Homozygous TREM2 p.T66M mutation has also been identified to cause FTD-like syndrome.344”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [344]
In the citing paper
“In addition to the R47H variant, further TREM2 variants have been revealed to be risk factors of AD or other CNS diseases, such as R62H (8,20), H157Y (25), Q33X, T66M and Y38C (26,27).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [27]
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Cites
The Sequence Alignment/Map format and SAMtools
Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., & 1000 Genome Project Data Processing Subgroup (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp352 · Cited by 62,041
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390
A framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,508
Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia
Rascovsky, K., Hodges, J. R., Knopman, D., Mendez, M. F., Kramer, J. H., Neuhaus, J., van Swieten, J. C., Seelaar, H., Dopper, E. G. P., Onyike, C. U., et al. (2011) · Brain · doi:10.1093/brain/awr179 · Cited by 5,221
Self-citationFrontotemporal lobar degeneration: A consensus on clinical diagnostic criteria
Neary, D., Snowden, J. S., Gustafson, L., Passant, U., Stuss, D., Black, S., Freedman, M., Kertesz, A., Robert, P. H., Albert, M., et al. (1998) · Neurology · doi:10.1212/wnl.51.6.1546 · Cited by 5,047
DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.011 · Cited by 4,936
A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.010 · Cited by 4,409
Self-citationAssociation of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., et al. (1998) · Nature · doi:10.1038/31508 · Cited by 3,498
Self-citationWeıntraub, S. (1990) · Archives of Neurology · doi:10.1001/archneur.1990.00530120075013 · Cited by 3,018
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Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569
TREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
Self-citationVariant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558
TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616
“T66M mutation has also been identified to cause FTD-like syndrome.(344) Recently, Xie et al.”
BackgroundMicroglia Biology: One Century of Evolving Concepts
Prinz, M., Jung, S., & Priller, J. (2019) · Cell · doi:10.1016/j.cell.2019.08.053 · Cited by 1,525
Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357
“TREM2 R47H is also associated with increased risk for Parkinson’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis (96,97,102,103).”
Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease
Prinz, M., & Priller, J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3722 · Cited by 1,329
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943
TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009093 · Cited by 798
Self-citationMicroglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response
Bachiller, S., Jiménez-Ferrer, I., Paulus, A., Yang, Y., Swanberg, M., Deierborg, T., & Boza‐Serrano, A. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00488 · Cited by 750
“TREM2related mutations (c.40 + 3delAGG, Q33X, Y38C, T66M, D86V, W198X) (Chouery et al., 2008; Giraldo et al., 2013; Guerreiro et al., 2013) have been found in individuals from six different families, presenting different forms of frontotemporal dementia [further, see review (Yeh et al., 2017)].”
BackgroundJay, T. R., Miller, C. M., Cheng, P. J., Graham, L. C., Bemiller, S., Broihier, M. L., Xu, G., Margevicius, D., Karlo, J. C., Sousa, G. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142322 · Cited by 682
“TREM2 variants such as the missense mutation Q33X (R. Guerreiro et al., 2013) and the FTD-related variants T66M and Y38C which impair protein maturation (Kleinberger et al., 2014), almost certainly impair TREM2 function.”
BackgroundInfluentialChiu, I. M., Morimoto, E. T. A., Goodarzi, H., Liao, J. T., O’Keeffe, S., Phatnani, H. P., Muratet, M., Carroll, M. C., Levy, S., Tavazoie, S., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.018 · Cited by 651
“Furthermore, Trem2, a microglia receptor that is upregulated during disease progression, was recently linked to AD susceptibility (Guerreiro et al., 2013a).”
The role of peripheral immune cells in the CNS in steady state and disease
Prinz, M., & Priller, J. (2017) · Nature Neuroscience · doi:10.1038/nn.4475 · Cited by 657
Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0296-9 · Cited by 555
Suárez‐Calvet, M., Kleinberger, G., Araque Caballero, M. Á., Brendel, M., Rominger, A., Alcolea, D., Fortea, J., Lleó, A., Blesa, R., Gispert, J. D., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201506123 · Cited by 522
“CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls.”
BackgroundCNS inflammation and neurodegeneration
Chitnis, T., & Weiner, H. L. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90609 · Cited by 470
“A rare missense mutation in the gene encoding TREM2 confers risk of late-onset AD (80, 81) and frontotemporal dementia (82), possibly due to impaired clearance of proteins by macrophages and microglia.”
BackgroundAlzheimer’s Disease Genetics: From the Bench to the Clinic
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473
TREM2, microglia, and neurodegenerative diseases
Yeh, F. L., Hansen, D. V., & Sheng, M. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.008 · Cited by 440
TREM2 variants: new keys to decipher Alzheimer disease pathogenesis
Colonna, M., & Wang, Y. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.7 · Cited by 418
TREM2 in Neurodegenerative Diseases
Jay, T. R., von Saucken, V. E., & Landreth, G. E. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0197-5 · Cited by 427
“Studies in families with frontotemporal dementia (FTD) [34] or frontotemporal lobar dementia (FTLD) found that PLOSL-associated TREM2 variants T66 M [35, 36], W198X [37], Q33X and Y38C [36] in either homozygosity or heterozygosity could also cause FTD [35–37] (Fig.”
BackgroundInfluentialRayaprolu, S., Mullen, B., Baker, M., Lynch, T., Finger, E., Seeley, W. W., Hatanpaa, K. J., Lomen-Hoerth, C., Kertesz, A., Bigio, E. H., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-19 · Cited by 404
“TREM2 is an important player in the immune response and loss-offunction mutations in TREM2 have been demonstrated to cause a spectrum of dementia-like phenotypes with or without bone cysts [3,5,7].”
InfluentialLee, C. Y. D., Daggett, A., Gu, X., Jiang, L.-L., Langfelder, P., Li, X., Wang, N., Zhao, Y., Park, C. S., Cooper, Y., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.002 · Cited by 396
“Rare variants in the microglia-enriched gene TREM2 confer high risk for LOAD (Guerreiro et al., 2013a; Jonsson et al., 2013; Sims et al., 2017).”
BackgroundInfluentialColonna, M. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00837-1 · Cited by 394
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Mazaheri, F., Snaidero, N., Kleinberger, G., Madore, C., Daria, A., Werner, G., Krasemann, S., Capell, A., Trümbach, D., Wurst, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201743922 · Cited by 351
Microglia: Architects of the Developing Nervous System
Frost, J. L., & Schafer, D. P. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.02.006 · Cited by 385
Soluble TREM2 induces inflammatory responses and enhances microglial survival
Zhong, L., Chen, X., Wang, T., Wang, Z., Liao, C., Wang, Z., Huang, R., Wang, D., Li, X., Wu, L., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160844 · Cited by 372
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deußing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · doi:10.7892/boris.125653 · Cited by 352
Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status
Piccio, L., Deming, Y., Del-Águila, J. L., Ghezzi, L., Holtzman, D. M., Fagan, A. M., Fenoglio, C., Galimberti, D., Borroni, B., & Cruchaga, C. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1533-5 · Cited by 337
“Furthermore, homozygous loss of function mutations in TREM2 are known to be the cause of NHD [28] and of some FTD-like cases [19].”
BackgroundElucidating the Role of TREM2 in Alzheimer’s Disease
Ulrich, J. D., Ulland, T. K., Colonna, M., & Holtzman, D. M. (2017) · Neuron · doi:10.1016/j.neuron.2017.02.042 · Cited by 325
Immune Signaling in Neurodegeneration
Hammond, T. R., Marsh, S. E., & Stevens, B. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.016 · Cited by 336
Coding variants in TREM2 increase risk for Alzheimer's disease
Jin, S. C., Benitez, B. A., Karch, C. M., Cooper, B., Skorupa, T., Carrell, D., Norton, J. B., Hsu, S., Harari, O., Cai, Y., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu277 · Cited by 314
TREM2 regulates microglial cell activation in response to demyelination in vivo
Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C. M., Galimberti, D., Olivecrona, G., Klein, R. S., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1388-1 · Cited by 296
“Furthermore, TREM2 mutations are associated with cases of frontotemporal dementia (FTD)-like syndrome without bone pathology [23].”
Genes associated with Alzheimer's disease: an overview and current status
Giri, M., Lü, Y., & Zhang, M. (2016) · Clinical Interventions in Aging · doi:10.2147/cia.s105769 · Cited by 311
Wunderlich, P., Glebov, K., Kemmerling, N., Tien, N. T., Neumann, H., & Walter, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.517540 · Cited by 296
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Bailey, C. C., DeVaux, L. B., & Farzan, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677286 · Cited by 303
Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease
Heslegrave, A., Heywood, W., Paterson, R., Magdalinou, N., Svensson, J., Johansson, P., Öhrfelt, A., Blennow, K., Hardy, J., Schott, J., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0071-x · Cited by 303
“Recently, dementia-like symptoms without bone involvement have been reported in patients with homozygous missense mutations in the TREM2 gene [4].”
BackgroundSelf-citationNeuroinflammation in frontotemporal dementia
Bright, F., Werry, E. L., Dobson-Stone, C., Piguet, O., Ittner, L. M., Halliday, G. M., Hodges, J. R., Kiernan, M. C., Loy, C. T., Kassiou, M., et al. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0231-z · Cited by 280
TREM2-Ligand Interactions in Health and Disease
Kober, D. L., & Brett, T. J. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.04.004 · Cited by 284
Suárez-Calvet, M., Araque Caballero, M. Á., Kleinberger, G., Bateman, R. J., Fagan, A. M., Morris, J. C., Levin, J., Danek, A., Ewers, M., Haass, C., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1767 · Cited by 272
Luo, W., Liu, W., Hu, X., Hanna, M., Caravaca, A., & Paul, S. M. (2015) · Scientific Reports · doi:10.1038/srep11161 · Cited by 241
TREM2 Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis
Cady, J., Koval, E. D., Benitez, B. A., Zaidman, C., Jockel-Balsarotti, J., Allred, P., Baloh, R. H., Ravits, J., Simpson, E., Appel, S. H., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6237 · Cited by 262
The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders
Carmona, S., Zahs, K., Wu, E., Dakin, K., Bras, J., & Guerreiro, R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30232-1 · Cited by 244
Self-citationKleinberger, G., Brendel, M., Mracsko, E. Z., Wefers, B., Groeneweg, L., Xiang, X., Focke, C., Deußing, M., Suárez‐Calvet, M., Mazaheri, F., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201796516 · Cited by 249
USP18 lack in microglia causes destructive interferonopathy of the mouse brain
Goldmann, T., Zeller, N., Raasch, J., Kierdorf, K., Frenzel, K., Ketscher, L., Basters, A., Staszewski, O., Brendecke, S. M., Spiess, A., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490791 · Cited by 223
“…as Csf1r in hereditary diffuse leukoencephalopathy with spheroids (Rademakers et al , 2012), CD33 in Alzheimer’s disease (Hollingworth et al , 2011; Naj et al , 2011), Trem2 in frontotemporal dementia (Guerreiro et al , 2013), and Tnfrsf1a and Irf8 in multiple sclerosis (De Jager et al , 2009).”
Neuroinflammation: Ways in Which the Immune System Affects the Brain
Ransohoff, R. M., Schafer, D. P., Vincent, A. C., Blachère, N. E., & Bar‐Or, A. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0385-3 · Cited by 257
“the recent direct implication of microglia in neurodegeneration, some rare polymorphic structural variants of TREM2 were shown to be risk factors for Alzheimer disease [18, 19], while other TREM2 variants were found to be associated to frontotemporal dementia [20].”
Sayed, F. A., Telpoukhovskaia, M., Kodama, L., Li, Y., Zhou, Y., Le, D., Hauduc, A., Ludwig, C., Gao, F., Clelland, C., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811411115 · Cited by 229
“The rare R47H missense variant in TREM2 is associated with increased risk for tauopathies (2, 3, 26, 28) and hyperphosphorylation 20 40 60 0.”
BackgroundTREM2 and the neuroimmunology of Alzheimer's disease
Hickman, S. E., & El Khoury, J. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.11.021 · Cited by 221
“However, homozygous loss-of-function mutations in TREM2 are associated with an autosomal recessive form of early-onset dementia affecting brain and bone termed Nasu– Hakola disease [45] and with a form of frontotemporal dementia without bone involvement [46].”
BackgroundKober, D. L., Alexander-Brett, J. M., Karch, C. M., Cruchaga, C., Colonna, M., Holtzman, M. J., & Brett, T. J. (2016) · eLife · doi:10.7554/elife.20391 · Cited by 238
Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia
Brownjohn, P. W., Smith, J., Solanki, R., Lohmann, E., Houlden, H., Hardy, J., Dietmann, S., & Livesey, F. J. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.003 · Cited by 193
“We obtained fibroblasts from a patient homozygous for the TREM2 T66Mmutation, associated with an FTD-like condition (Guerreiro et al., 2013b) (T66M/T66M), two unaffected family members carrying a single copy of the T66Mmutation (wt/T66M), and a patient homozygous for the recently described…”
BackgroundSelf-citationLiu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214
“In addition to the R47H variant, further TREM2 variants have been revealed to be risk factors of AD or other CNS diseases, such as R62H (Jin et al. 2014; Sims et al. 2017), H157Y (Jiang et al. 2016), Q33X, T66M and Y38C (Guerreiro et al. 2013a; Guerreiro et al. 2013c).”
BackgroundSelf-citationMicroglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer’s Disease Genetics
Podleśny-Drabiniok, A., Marcora, E., & Goate, A. M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.002 · Cited by 211
TREM2, microglia, and Alzheimer’s disease.
Qin, Q., Teng, Z., Liu, C., Li, Q., Yin, Y., & Tang, Y. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111438 · Cited by 219
Lill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L., Liu, T., Lassen, C. F., Meissner, E., et al. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.12.009 · Cited by 205
“TREM2 was earlier reported to harbor autosomal-recessive mutations causing NasuHakola disease [8], a neurodegenerative disorder characterized by progressive presenile dementia and cystic bone lesions, and underlying familial FTLD [9].”
The Role of APOE and TREM2 in Alzheimer′s Disease—Current Understanding and Perspectives
Wolfe, C. M., Fitz, N. F., Nam, K. N., Lefterov, I. M., & Koldamova, R. P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010081 · Cited by 201
“1 in the TREM gene cluster near other TREM and TREM-like genes: TREML1, TREM2, TREML2, TREML3, TREML4, and TREM1 [68,69].”
BackgroundInfluentialTREM2 in CNS homeostasis and neurodegenerative disease
Painter, M. M., Atagi, Y., Liu, C.-C., Rademakers, R., Xu, H., Fryer, J. D., & Bu, G. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0040-9 · Cited by 169
“(non-NHD/PLOSL) clinical presentation [12].”
BackgroundInfluentialCuyvers, E., Bettens, K., Philtjens, S., Langenhove, T. V., Gijselinck, I., van der Zee, J., Engelborghs, S., Vandenbulcke, M., Dongen, J. V., Geerts, N., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.009 · Cited by 185
Innate immune activation in neurodegenerative diseases
Castro‐Gomez, S., & Heneka, M. T. (2024) · Immunity · doi:10.1016/j.immuni.2024.03.010 · Cited by 176
TREM2 is associated with the risk of Alzheimer's disease in Spanish population
Benitez, B. A., Cooper, B., Pastor, P., Jin, S.-C., Lorenzo, E., Cervantes, S., & Cruchaga, C. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.018 · Cited by 163
“However, 2 independent studies recently reported that a nonsynonymous variant in TREM2, rs75932628 (encoding R47H), is strongly associated with AD (Guerreiro et al., 2013a; Jonsson et al., 2012).”
InfluentialGarcia-Reitboeck, P., Phillips, A., Piers, T. M., Villegas-Llerena, C., Butler, M., Mallach, A., Rodrigues, C., Arber, C. E., Heslegrave, A., Zetterberg, H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.094 · Cited by 162
Self-citationRyan, K. J., White, C. C., Patel, K. R., Xu, J., Olah, M., Replogle, J. M., Frangieh, M., Cimpean, M., Winn, P. A., McHenry, A., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aai7635 · Cited by 159
Guerreiro, R., Bilgic, B., Guven, G., Brás, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.005 · Cited by 158
“…cases with homozygous mutations in TREM2 have been described to present atypical phenotypes resembling behavioral variant frontotemporal dementia (bvFTD) and lacking stage (2) of the clinical picture described previously (Chouery et al., 2008; Giraldo et al., 2013; Guerreiro et al., 2013b).”
BackgroundResultInfluentialSelf-citationGenetics of Alzheimer's Disease
Guerreiro, R. J., & Hardy, J. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0295-9 · Cited by 168
“By performing autozygosity and exome sequencing analyses in Turkish dementia families we identified TREM2 homozygous mutations causing frontotemporal dementia [23].”
MethodSelf-citationGenetics of FTLD : overview and what else we can expect from genetic studies
Pottier, C., Ravenscroft, T. A., Sanchez‐Contreras, M., & Rademakers, R. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13622 · Cited by 148
“…a known cause of Nasu Hakola disease, have also been described in patients with atypical FTLD characterized by very young onset age, the presence of seizures and parkinsonism and extensive white matter lesions on brain imaging (Le Ber et al. 2014, Guerreiro et al. 2013a, Guerreiro et al. 2013b).”
TREM2 is associated with increased risk for Alzheimer’s disease in African Americans
Jin, S. C., Carrasquillo, M. M., Benitez, B. A., Skorupa, T., Carrell, D., Patel, D., Lincoln, S., Krishnan, S., Kachadoorian, M., Reitz, C., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0016-9 · Cited by 153
“its homozygous state in the proband of a Turkish pedigree with an FTD-like syndrome [16] and also observed in its”
BackgroundHeterozygous TREM2 mutations in frontotemporal dementia
Borroni, B., Ferrari, F., Galimberti, D., Nacmias, B., Barone, C., Bagnoli, S., Fenoglio, C., Piaceri, I., Archetti, S., Bonvicini, C., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.017 · Cited by 173
“Furthermore, in human control brain, TREM2 was expressed at higher levels in the hippocampus and neocortex (Guerreiro et al., 2013a), and this pattern of Table 2 In silico analyses of the amino acid changes found in the analyzed sample In silico software Q33X R47H R62H T66M D87N T96K R98W S116C…”
BackgroundInfluentialGiraldo, M., Lopera, F., Siniard, A. L., Corneveaux, J. J., Schrauwen, I., Carvajal, J., Muñoz, C., Ramirez-Restrepo, M., Gaiteri, C., Myers, A. J., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.02.016 · Cited by 147
“Recently, a variant in TREM2 (rs75932628) has also been implicated as a risk factor for both early-onset and late-onset Alzheimer's disease (Jonsson et al., 2012; Pottier et al., 2013; R. Guerreiro et al., 2012).”
BackgroundResultInfluentialThe clinical spectrum of sporadic and familial forms of frontotemporal dementia
Woollacott, I., & Rohrer, J. D. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13654 · Cited by 163
“Heterozygous TREM2 variants have recently been described as a risk factor for AD (Benitez et al. 2013; Guerreiro et al. 2013b; Jonsson et al. 2013; Pottier et al. 2013), but studies have been mixed as to whether this is also the case for FTD (Lattante et al. 2013; Rayaprolu et al. 2013; Borroni et…”
BackgroundSelf-citationPrice, B. R., Sudduth, T. L., Weekman, E. M., Johnson, S. N., Hawthorne, D., Woolums, A. E., & Wilcock, D. M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01915-0 · Cited by 146
Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease
Henjum, K., Almdahl, I. S., Årskog, V., Minthon, L., Hansson, O., Fladby, T., & Nilsson, L. N. G. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0182-1 · Cited by 145
“R47H] and frontotemporal dementia mutations [25] are most probably loss of function, resulting in reduced TREM2 cell surface localization and shedding [18].”
BackgroundKorvatska, O., Leverenz, J. B., Jayadev, S., McMillan, P., Kurtz, I., Guo, X., Rumbaugh, M., Matsushita, M., Girirajan, S., Dorschner, M. O., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.0979 · Cited by 137
Soluble TREM2: Innocent bystander or active player in neurological diseases?
Filipello, F., Goldsbury, C., You, S. F., Locca, A., Karch, C. M., & Piccio, L. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105630 · Cited by 134
Microglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
Condello, C., Yuan, P., & Grutzendler, J. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.007 · Cited by 131
Götzl, J. K., Brendel, M., Werner, G., Parhizkar, S., Sebastian Monasor, L., Kleinberger, G., Colombo, A., Deussing, M., Wagner, M., Winkelmann, J., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809711 · Cited by 118
“…the progranulin (PGRN) protein; Baker et al, 2006; Cruts & Van Broeckhoven, 2008; Zhang et al, 2014; Gotzl et al, 2016; Lui et al, 2016) and TREM2 (Guerreiro et al, 2013; Jonsson & Stefansson, 2013; Jonsson et al, 2013; Rayaprolu et al, 2013; Borroni et al, 2014; Cuyvers et al, 2014; Ulrich et…”
BackgroundCheng, Q., Danao, J., Talreja, S., Wen, P. H., Yin, J., Sun, N., Li, C.-M., Chui, D., Tran, D. T., Koirala, S., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.001848 · Cited by 129
“More recently, variants in the TREM2 gene have been linked to increased risk for Alzheimer’s disease (AD) and other forms of dementia including frontotemporal dementia (5-7).”
BackgroundNeuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
Bevan-Jones, W. R., Cope, T. E., Jones, P. S., Kaalund, S. S., Passamonti, L., Allinson, K., Green, O., Hong, Y. T., Fryer, T. D., Arnold, R., et al. (2020) · Brain · doi:10.1093/brain/awaa033 · Cited by 124
“…across the FTD spectrum, corroborating suggestions from epidemiological (Lant et al., 2014; Venneti et al., 2008), genetic (Broce et al., 2018; Guerreiro et al., 2013; Rayaprolu et al., 2013), imaging (Cagnin, Rossor, Sampson, MacKinnon, & Banati, 2004; Miyoshi et al., 2010) and animal…”
BackgroundPhenotypic Heterogeneity of Monogenic Frontotemporal Dementia
Benussi, A., Padovani, A., & Borroni, B. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00171 · Cited by 129
Aguzzi, A., & Zhu, C. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90605 · Cited by 122
Parkinsonism, movement disorders and genetics in frontotemporal dementia
Baizabal-Carvallo, J. F., & Jankovic, J. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.14 · Cited by 121
Slattery, C. F., Beck, J. A., Harper, L., Adamson, G., Abdi, Z., Uphill, J., Campbell, T., Druyeh, R., Mahoney, C. J., Rohrer, J. D., et al. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.05.1751 · Cited by 119
Self-citationGenetic targeting of microglia
Wieghofer, P., Knobeloch, K., & Prinz, M. (2014) · Glia · doi:10.1002/glia.22727 · Cited by 118
Jiang, T., Tan, L., Zhu, X.-C., Zhou, J.-S., Cao, L., Tan, M.-S., Wang, H.-F., Chen, Q., Zhang, Y.-D., & Yu, J.-T. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.08.019 · Cited by 111
Ruiz, A., Dols-Icardo, O., Bullido, M. J., Pastor, P., Rodríguez-Rodríguez, E., López de Munain, A., de Pancorbo, M. M., Pérez-Tur, J., Álvarez, V., Antonell, A., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.08.011 · Cited by 118
Jiang, T., Yu, J., Zhu, X., & Tan, L. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8424-8 · Cited by 122
“Besides, Chouery and colleagues reported a homozygous mutation in the 5′ consensus donor splice site in intron 1 of TREM2 that led to early-onset dementia without bone cysts in a Lebanese family [27], and three homozygousmutations in TREM2 have recently been revealed in three Turkish probands with frontotemporal demen…”
BackgroundResultCentral nervous system myeloid cells as drug targets: current status and translational challenges
Biber, K. P. H., Möller, T., Boddeke, E., & Prinz, M. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.14 · Cited by 111
Fassler, M., Rappaport, M., Benaim, C., & George, J. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01980-5 · Cited by 112
“Whereas heterozygous variants in TREM2 are associated with AD [2, 3, 8], homozygous variants in TREM2 or its binding partner DAP12/TYROBP cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease (NHD).”
BackgroundMicroglia in Alzheimer’s disease: A target for immunotherapy
Wang, S., & Colonna, M. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr0818-319r · Cited by 106
Radford, R. A. W., Morsch, M., Rayner, S. L., Cole, N. J., Pountney, D. L., & Chung, R. S. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00414 · Cited by 105
“Interestingly homozygous and compound heterozygous mutations are linked to a familial FTD-like disorder without bone involvement (Kaneko et al., 2010; Guerreiro et al., 2013; Borroni et al., 2014).”
Aminophospholipids are signal-transducing TREM2 ligands on apoptotic cells
Shirotani, K., Hori, Y., Yoshizaki, R., Higuchi, E., Colonna, M., Saito, T., Hashimoto, S., Saito, T., Saido, T. C., & Iwata, N. (2019) · Scientific Reports · doi:10.1038/s41598-019-43535-6 · Cited by 116
Homozygous TREM2 mutation in a family with atypical frontotemporal dementia
Ber, I. L., de Septenville, A. L., Guerreiro, R. J., Brás, J., Camuzat, A., Caroppo, P., Lattante, S., Couarch, P., Kabashi, E., Bouya-Ahmed, K., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.04.010 · Cited by 99
“…TREM2 mutations have been identified in rare families of Turkish and Colombian origin with autosomal recessive behavioral variant of frontotemporal lobar degeneration (FTLD) but without any clinical or radiological evidence of bone involvement (Giraldo et al., 2013; Guerreiro et al., 2013a, 2013b).”
BackgroundResultInfluentialSelf-citationJendresen, C., Årskog, V., Daws, M. R., & Nilsson, L. N. G. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0835-4 · Cited by 94
The Evolution of Genetics: Alzheimer’s and Parkinson’s Diseases
Singleton, A., & Hardy, J. (2016) · Neuron · doi:10.1016/j.neuron.2016.05.040 · Cited by 94
Self-citationArreola, M. A., Soni, N., Crapser, J. D., Hohsfield, L. A., Elmore, M. R. P., Matheos, D. P., Wood, M. A., Swarup, V., Mortazavi, A., & Green, K. N. (2021) · Science Advances · doi:10.1126/sciadv.abg1601 · Cited by 92
Vps35-dependent recycling of Trem2 regulates microglial function
Yin, J., Liu, X., He, Q., Zhou, L., Yuan, Z., & Zhao, S. (2016) · Traffic · doi:10.1111/tra.12451 · Cited by 90
“Many mutations of Trem2 have been involved in several neurodegenerative diseases.(6,10,13,41,42) Recently, 2 independent groups investigated how Trem2 missense mutations affected Trem2 func-”
A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature
Dardiotis, E., Siokas, V., Pantazi, E., Dardioti, M., Rikos, D., Xiromerisiou, G., Markou, A., Papadimitriou, D. A., Speletas, M. G., & Hadjigeorgiou, G. M. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.01.015 · Cited by 88
Park, J., Ji, I. J., An, H. J., Kang, M., Kang, S., Kim, D., & Yoon, S. (2015) · Traffic · doi:10.1111/tra.12264 · Cited by 90
“Recently, several TREM2 mutations have also been reported to cause a fronto-temporal dementia (FTD)-like syndrome without bone pathology (7,8).”
BackgroundOligodendrocytes in Alzheimer’s disease pathophysiology
Kedia, S., & Simons, M. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01873-x · Cited by 86
“One example is TREM2 , where rare loss-of-function genetic variants have been identified in the coding region of a gene exclusively expressed in microglia, thereby tripling the risk of AD 68,69 .”
Shifting paradigms: The central role of microglia in Alzheimer’s disease
Schwabe, T., Srinivasan, K., & Rhinn, H. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104962 · Cited by 84
“1% of the general population, was found to be associated with AD risk through genome-wide scans and targeted sequencing or imputation (Guerreiro et al., 2013; Jonsson et al., 2013).”
BackgroundWalter, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.704981 · Cited by 80
Metadata
- Authors
- Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, J. R., Rohrer, J. D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., Emre, M., Singleton, A., & Hardy, J.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2013-01-01
- Volume
- 70
- Issue
- 1
- Pages
- 78
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4001789
- OpenAlex
- W1984557585
- Cited by
- 374
- References
- 27
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 20 · 2023: 17 · 2022: 12 · 2021: 39 · 2020: 34 · 2019: 22 · 2018: 32 · 2017: 37 · 2016: 29 · 2015: 40 · 2014: 26 · 2013: 21
- FWCI
- 27.37
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (089698)
- National Institutes of Health
- National Institute on Aging (Z01AG000950)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- TREM2, frontotemporal dementia, homozygous mutation, genetic diagnosis, white matter abnormalities, behavior change, cognitive impairment, exome sequencing, Turkish patients
- MeSH terms
- Adult, Humans, Male, Membrane Glycoproteins, Mutation, Receptors, Immunologic, Risk Factors, Syndrome, Frontotemporal Dementia, Exome
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