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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]
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“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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The Role of Microglia in Sporadic Alzheimer’s Disease
Streit, W. J., Khoshbouei, H., & Bechmann, I. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201248 · Cited by 87
“…a rare coding variant in the TREM2 gene is present in approximatively 0.1% of the general population found to be associated with increased AD risk [6, 7], consistent with prior work showing that TREM2 is among the highest upregulated mRNAs and the protein colocalizes with microglia at plaques in…”
InfluentialAn overview of the genes and biomarkers in Alzheimer’s disease
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“This has become an increasingly pressing challenge as rare variants in TREM2 have been identified as risk factors in Alzheimer’s disease and frontotemporal dementia [9, 37, 38, 42, 54].”
BackgroundAPOE4 confers transcriptomic and functional alterations to primary mouse microglia
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“, TREM2, PLCG2, and ABI3) have been associated with AD (Guerreiro et al., 2013; Jonsson et al., 2013; Sims et al., 2017).”
BackgroundTREM2 expression in the human brain: a marker of monocyte recruitment?
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“The importance of TREM2 in brain function has been illustrated by the autosomal recessive disorder Nasu-Hakola disease (NHD) due to homozygous loss-of-function mutations in the TREM2 gene (11, 32), in which affected people develop a presenile frontotemporal dementia with sclerosing leukoencephalopathy and polycystic l…”
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“In addition, a subset of loss-of-function TREM2 variants was found to predispose a frontotemporal dementia-like syndrome in the absence of apparent bone involvement [84].”
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Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice
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“…TREM2 mutations, including early stop codons (E14X, Q33X, W44X, W78X) [24–27] and mis-sense mutations in the immunoglobulin-like ectodomain (Y38C, W50C, T66M, V126G) [24, 28, 29], are primarily linked to NHD, a rare disorder characterized by early-onset dementia, demyelination, and bone cysts.”
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Microglia, Trem2, and Neurodegeneration
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“Another mutation in Trem2, T66M variant was first described in a Turkish patient with frontotemporal dementia (FTD) (Guerreiro and others 2013b).”
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“…(TLR)-mediated inflammatory cytokines, and promotes microglial phagocytosis of neuronal cell debris and bacteria (Takahashi et al., 2005, 2007; Hamerman et al., 2006; Turnbull et al., 2006; Neumann and Takahashi, 2007; Hsieh et al., 2009; N’Diaye et al., 2009; Ito and Please cite this article…”
Mapping neuroinflammation in frontotemporal dementia with molecular PET imaging
Zhang, J. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0236-5 · Cited by 62
“Genes related to microglial activation (for example, a variant of the triggering receptor expressed on myeloid cells 2 (TREM2)) have now been associated with FTD [29,30].”
BackgroundWang, M., Tang, G., Zhou, C., Guo, H., Hu, Z., Hu, Q., & Li, G. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110387 · Cited by 62
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Rare TREM2 variants associated with Alzheimer’s disease display reduced cell surface expression
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“These include missense mutations such as Y38C, T66M and D86V that occur within the Ig-like domain of TREM2 [32, 35, 36].”
BackgroundDivergent Neuroinflammatory Regulation of Microglial TREM Expression and Involvement of NF-κB
Owens, R., Grabert, K., Davies, C. L., Alfieri, A., Antel, J. P., Healy, L. M., & McColl, B. W. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00056 · Cited by 62
“Recent studies have also revealed that homozygous TREM2 mutations cause a frontotemporal dementia-like syndrome in the absence of bone pathology (Giraldo et al., 2013; Guerreiro et al., 2013a; Le Ber et al., 2014).”
BackgroundThe Role of Microglia in Prion Diseases: A Paradigm of Functional Diversity
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Targeting Alzheimer's disease with gene and cell therapies
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Exome sequencing greatly expedites the progressive research of Mendelian diseases
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“Frontotemporal dementia-like syndrome without bone involvement AR TREM2 [161]”
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“Trem2 is a scavenger receptor found on the surface of myeloid cells, and TREM2 mutations leading to impaired phagocytic activity [42] are strong risk factors for multiple neurodegenerative diseases, including ALS [10, 27, 39].”
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“The same type of mutations (and in some cases the same exact mutations) have been described in patients presenting with frontotemporal dementia, but with no associated bone phenotypes (50,60).”
Self-citationCSF sTREM2 in delirium—relation to Alzheimer’s disease CSF biomarkers Aβ42, t-tau and p-tau
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“TREM2 variants have been associated with frontotemporal dementia cases of recessive inheritance [39, 40].”
Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes
Thelen, M., Razquín, C., Hernández, I., Gorostidi, A., Sánchez‐Valle, R., Ortega‐Cubero, S., Wolfsgruber, S., Drichel, D., Fließbach, K., Duenkel, T., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.018 · Cited by 53
More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer's disease risk
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“Discussion A rare TREM2 (R47H) variant that considerably increases LOAD risk has been identified in populations of European descent (Benitez et al., 2013, Giraldo et al., 2013, Guerreiro et al., 2013, Jonsson et al., 2013, Gonzalez et al., 2013).”
BackgroundInfluentialIn Vivo Imaging of Microglial Calcium Signaling in Brain Inflammation and Injury
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From Common to Rare Variants: The Genetic Component of Alzheimer Disease
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Tipping points in neurodegeneration
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“Among these, the variation found in TREM2 is of exceptional importance because it triples disease risk and occurs in the coding region of a gene expressed exclusively in microglia in the brain.(72,73) The substantial effect size of the genetic variation enabled subsequent functional follow-up analyses of the role of T…”
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“Interestingly, it is only individuals that are heterozygous for TREM2 that are at risk for AD: homozygous, autosomal recessive mutations for TREM2 result in The Nasu-Hakola disease in some individuals characterized by bone cysts and dementia [75], while resulting in fronttemporal dementia without bone disease in other…”
BackgroundKokiko-Cochran, O., Ransohoff, L., Veenstra, M., Lee, S., Saber, M., Sikora, M., Teknipp, R., Xu, G., Bemiller, S., Wilson, G., et al. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.3970 · Cited by 49
Progranulin Protein Levels in Cerebrospinal Fluid in Primary Neurodegenerative Dementias
Morenas‐Rodríguez, E., Cervera‐Carles, L., Vilaplana, E., Alcolea, D. A., Carmona‐Iragui, M., Dols‐Icardo, O., Nogué, R. R., Muñoz, L., Sala, I., Sánchez‐Saudinós, M. B., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150746 · Cited by 53
Neocortical and hippocampal TREM2 protein levels during the progression of Alzheimer's disease
Perez, S. E., Nadeem, M., He, B., Miguel, J. C., Malek‐Ahmadi, M. H., Chen, K., & Mufson, E. J. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.02.012 · Cited by 51
“…disease (Hakola, 1072; Nasu et al., 1973), which is associated with a form of neurodegeneration leading to dementia (Bianchin et al., 2004; Verloes et al., 1997) and a form of frontotemporal dementia (Chouery et al., 2008; Giraldo et al., 2013; Guerreiro et al., 2013a; Le Ber et al., 2014).”
BackgroundInfluentialKnapskog, A., Henjum, K., Idland, A., Eldholm, R. S., Persson, K., Saltvedt, I. T., Watne, L. O., Engedal, K., & Nilsson, L. N. G. (2020) · Scientific Reports · doi:10.1038/s41598-020-72878-8 · Cited by 53
Alzheimer's disease genes and autophagy
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Frontobasal gray matter loss is associated with the TREM2 p.R47H variant
Luis, E. O., Ortega-Cubero, S., Lamet, I., Razquin, C., Cruchaga, C., Benitez, B. A., Lorenzo, E., Irigoyen, J., Pastor, M. A., & Pastor, P. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.007 · Cited by 47
“…of brains with TREM2 rare variants including p.R47H revealed that all were in advanced AD (Braak stage 6) and most had typical fi ndings with no distinguishing features except for the presence of mild Lewy body and TAR DNA-binding protein 43 disease in 2 of them (Guerreiro et al., 2013a, 2013b).”
InfluentialMicroglia Phenotypes Converge in Aging and Neurodegenerative Disease
Candlish, M., & Hefendehl, J. K. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.660720 · Cited by 49
Differential Modulation of TREM2 Protein during Postnatal Brain Development in Mice
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“Recently, the role of microglia and perinatal inflammation has been associated with certain psychiatric disorders [38,68,69,70] while loss-of-function mutation of TREM2 has been associated with several neurodegenerative disorders or dementia [71,72,73,74].”
BackgroundThe Role of TREM2 in Alzheimer’s Disease and Other Neurological Disorders
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Mechanistic insights into the deleterious roles of Nasu-Hakola disease associated TREM2 variants
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Microglia in Health and Diseases: Integrative Hubs of the Central Nervous System (CNS)
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Genetic architecture of common non-Alzheimer’s disease dementias
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TREM2 analysis and increased risk of Alzheimer's disease
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“Recently, a variant in the TREM2 gene (rs75932628) was identified as a novel risk factor for late-onset AD in 2 independent studies (Guerreiro et al., 2013a; Jonsson et al., 2013), and this has since been replicated by other further studies in different populations (Benitez et al., 2013; Giraldo et…”
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Genetic risk factors for Alzheimer disease: emerging roles of microglia in disease pathomechanisms
Takatori, S., Wang, W., Iguchi, A., & Tomita, T. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-05542-4_5 · Cited by 44
Genetics of frontotemporal lobar degeneration: An up-date and diagnosis algorithm
Ber, I. L. (2013) · Revue Neurologique · doi:10.1016/j.neurol.2013.07.014 · Cited by 52
Crook, A., Williams, K. L., Adams, L., Blair, I. P., & Rowe, D. B. (2017) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2017.1332079 · Cited by 44
“Whole genome sequencing technology and recruitment of large cohorts of affected cases is significantly increasing our understanding of the genetic basis of both sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (1,2).”
BackgroundNeuroimaging in genetic frontotemporal dementia and amyotrophic lateral sclerosis
Häkkinen, S., Chu, S. A., & Lee, S. E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105063 · Cited by 42
“TREM2 carriers with a pure FTD diagnosis exhibit frontal and/or temporal atrophy with parietal and hippocampal involvement along with extensive white matter lesions and reduced thickness of the corpus callosum (Giraldo et al., 2013; Guerreiro et al., 2013; Le Ber et al., 2014).”
Regulation of microglial survival and proliferation in health and diseases
Ulland, T. K., Wang, Y., & Colonna, M. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2016.03.011 · Cited by 43
Glebov, K., Wunderlich, P., Karaca, I., & Walter, J. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0479-9 · Cited by 44
“Interestingly, TREM2 variants have recently been associated with late-onset Alz-heimer ’ s disease (AD) and frontotemporal lobe dementia (FTD) [8 – 10].”
Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease
Khani, M., Gibbons, E., Bras, J., & Guerreiro, R. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00505-9 · Cited by 39
“In 2013, after identifying triggering receptor expressed on myeloid cells 2 ( TREM2 ) homozygous mutations as the cause of atypical frontotemporal dementia in three Turkish families [40] we expanded the genetic analyses of this gene to include other dementias.”
BackgroundSelf-citationSirkis, D. W., Aparicio, R. E., & Schekman, R. W. (2017) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-06-0423 · Cited by 42
Dean, H. B., Roberson, E. D., & Song, Y. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01252 · Cited by 43
“In contrast, the FTD syndrome without bone involvement tends to arise when patients have some remaining TREM2 activity, including late truncations—such as W198X (8)—or in a variety of point mutations—including T66M (6), D86V (7), and T96K (10) (Figure 1A).”
BackgroundNeuroinflammation in Prion Disease
Li, B., Chen, M., & Zhu, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042196 · Cited by 51
Neuroinflammation — using big data to inform clinical practice
Dendrou, C. A., McVean, G., & Fugger, L. H. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.171 · Cited by 43
“Similarly, genetic variation in the Triggering receptor expressed on myeloid cells 2 ( TREM2 ) gene, which is involved in microglial activity, is associated with AD 37-41 and other neurological disorders, including Nasu–Hakola disease 42 , frontotemporal dementia 43,44 , PD 44 and ALS 45 .”
BackgroundGlial cells and adaptive immunity in frontotemporal dementia with tau pathology
Hartnell, I. J., Blum, D. L., Nicoll, J. A. R., Dorothée, G., & Boche, D. (2020) · Brain · doi:10.1093/brain/awaa457 · Cited by 41
Monocyte-derived macrophages act as reinforcements when microglia fall short in Alzheimer’s disease
Abellanas, M. A., Purnapatre, M., Burgaletto, C., & Schwartz, M. (2025) · Nature Neuroscience · doi:10.1038/s41593-024-01847-5 · Cited by 40
“Genetic TREM2 variants have been associated with an increased risk of AD 62,63 .”
Modeling gut-brain interactions in zebrafish
de Abreu, M. S., Giacomini, A. C. V. V., Sysoev, M., Demin, K. A., Alekseeva, P. A., Spagnoli, S., & Kalueff, A. V. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2019.03.003 · Cited by 41
NIAGADS: The NIA Genetics of Alzheimer's Disease Data Storage Site
Kuzma, A. B., Valladares, O., Cweibel, R., Greenfest‐Allen, E., Childress, D. M., Malamon, J. S., Gangadharan, P., Zhao, Y., Qu, L., Leung, Y. Y., et al. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.08.018 · Cited by 38
“Rare protective [3] and susceptibility variants [4] were also found by genome resequencing.”
BackgroundGeniposide Enhances Macrophage Autophagy through Downregulation of TREM2 in Atherosclerosis
Xu, Y., Liu, X., Cheng, S., He, P., Hong, M., Chen, Y., Zhou, F., & Jia, Y. (2020) · The American Journal of Chinese Medicine · doi:10.1142/s0192415x20500913 · Cited by 39
Alzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease
Golde, T. E., Streit, W. J., & Chakrabarty, P. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt178 · Cited by 39
“us, similar to the mutations in the same region that cause PLOSL, it is hypo thesized that the variants in TREM2 associated with AD cause loss of function or partial loss of function, reduc ing ligand binding and downstream signaling [18,30].”
Next Generation Sequencing Analysis in Early Onset Dementia Patients
Bonvicini, C., Initiative, A. D. N., Scassellati, C., Benussi, L., Maria, E. D., Maj, C., Ciani, M., Fostinelli, S., Mega, A., Bocchetta, M., et al. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180482 · Cited by 37
“microglial receptor, can lead to aberrant innate immune cell signalling, contributing to the initiation and propagation of several neurodegenerative phenotypes [72-83], including LBD.”
BackgroundGiannoccaro, M. P., Bartoletti‐Stella, A., Piras, S., Pession, A., Massis, P. D., Oppi, F., Maserati, M. S., Pasini, E., Baiardi, S., Avoni, P., et al. (2017) · Journal of Neurology · doi:10.1007/s00415-017-8540-x · Cited by 37
CELF2 regulates the species-specific alternative splicing of TREM2
Yanaizu, M., Washizu, C., Nukina, N., Satoh, J., & Kino, Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-75057-x · Cited by 32
The Primary Microglial Leukodystrophies: A Review
Ferrer, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116341 · Cited by 35
Recent advances in the molecular genetics of frontotemporal lobar degeneration
Rainero, I. (2017) · Functional Neurology · doi:10.11138/fneur/2017.32.1.007 · Cited by 34
“In January 2013, a study identified different homozygous mutations in TREM2 in three Turkish probands among 44 identified with FTLD spectrum-like disease (Guerreiro et al., 2013).”
BackgroundTMEM59 interacts with TREM2 and modulates TREM2-dependent microglial activities
Liu, Z., Ning, J., Zheng, X., Meng, J., Han, L., Zheng, H., Zhong, L., Chen, X., Zhang, X., Luo, H., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-02874-3 · Cited by 35
Güven, G., Lohmann, E., Brás, J., Gibbs, J. R., Gurvit, H. I., Bılgıç, B., Hanagasi, H. A., Rizzu, P., Heutink, P., Emre, M., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162592 · Cited by 33
“When these data is combined with data we have previously published [15, 16, 17] we conclude that among 105 dementia patients, 5.”
BackgroundMethodSelf-citationKorvatska, O., Kiianitsa, K., Ratushny, A. V., Matsushita, M. M., Beeman, N. E., Chien, W., Satoh, J., Dorschner, M. O., Keene, C. D., Bammler, T. K., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.559342 · Cited by 31
“In PLOSL, mutations that inactivate TREM2, including premature stop codons (49, 50), splice-site mutations (22, 51), and the missense variants D134G, K186N (4), Y38C, T66M, and V126G (5, 52, 53), have a recessive mode of inheritance.”
BackgroundEdwin, T. H., Henjum, K., Nilsson, L. N. G., Watne, L. O., Persson, K., Eldholm, R. S., Saltvedt, I. T., Halaas, N. B., Selbæk, G., Engedal, K., et al. (2020) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12128 · Cited by 35
Microglial TREM2 in amyotrophic lateral sclerosis
Xie, M., Zhao, S., Bosco, D. B., Nguyen, A. T., & Wu, L. (2021) · Developmental Neurobiology · doi:10.1002/dneu.22864 · Cited by 35
“…factors in a spectrum of neurodegenerative disease, including Alzheimer’s disease (AD) (Giraldo et al., 2013; R. Guerreiro et al., 2013; Jonsson et al., 2013), frontotemporal dementia (FTD) (R. J. Guerreiro et al., 2013; Le Ber et al., 2014), and Parkinson’s disease (PD) (Rayaprolu et al., 2013).”
BackgroundNegative regulation of TREM2-mediated C9orf72 poly-GA clearance by the NLRP3 inflammasome
Shu, X., Chen, W., Tu, W.-Y., Zhong, K., Qi, S., Wang, A., Bai, L., Zhang, S.-X., Luo, B., Xu, Z., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112133 · Cited by 33
A nonsense mutation in PRNP associated with clinical Alzheimer's disease
Guerreiro, R. J., Brás, J., Wojtas, A., Rademakers, R., Hardy, J., & Graff-Radford, N. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.05.013 · Cited by 32
“…E E4 allele increases the risk of AD by 3-to 15-fold, although several genetic loci (CLU, PICALM, CR1, BIN1, MS4A, CD2AP, CD33, EPHA1, ABCA7, CD2AP, HLA-DRB5/DRB1, SORL1, PTK2B, SLC24A4, ZCWPW1, CELF1, FERMT2, CASS4, INPP5D, MEF2C, NME8) have a low effect on disease risk (Guerreiro et al., 2013a).”
Self-citationEvidence of CNS β-amyloid deposition in Nasu-Hakola disease due to the TREM2 Q33X mutation
Ghezzi, L., Carandini, T., Arighi, A., Fenoglio, C., Arcaro, M., Riz, M. A. D., Pietroboni, A. M., Fumagalli, G., Basilico, P., Calvi, A., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000004747 · Cited by 31
Obesity and genomics: role of technology in unraveling the complex genetic architecture of obesity
Apalasamy, Y. D., & Mohamed, Z. (2015) · Human Genetics · doi:10.1007/s00439-015-1533-x · Cited by 35
Biallelic mutations in NRROS cause an early onset lethal microgliopathy
Smith, C., McColl, B. W., Patir, A., Barrington, J., Armishaw, J., Clarke, A., Eaton, J., Hobbs, V., Mansour, S., Nolan, M. A., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02137-7 · Cited by 31
Contributions of triggering-receptor-expressed-on-myeloid-cells-2 to neurological diseases
Han, J., Wang, M., Ren, M., & Lou, H. (2017) · International Journal of Neuroscience · doi:10.1080/00207454.2016.1264072 · Cited by 30
“yet the level in the cerebellum is low [12].”
BackgroundRoles of TREM2 in Alzheimer’s disease
Qi, X., Zhu, K., Ke, W., Wang, J., Mao, S., & Chen, G. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00515-3 · Cited by 38
“Related diseases CSF sTREM2 level Q33X Nasu-Hakola disease [237], frontotemporal dementia [241] Reduced [223] Y38C Frontotemporal dementia [241] N/A R47H Alzheimer’s disease [10, 11] Increased [209, 223] W50C Nasu-Hakola disease [238] N/A R62H Alzheimer’s disease [18] No change [223] T66M…”
Companys‐Alemany, J., Turcu, A. L., Vázquez, S., Pallàs, M., & Griñán‐Ferré, C. (2022) · Scientific Reports · doi:10.1038/s41598-022-22963-x · Cited by 31
Clayton, E. L., Mancuso, R., Nielsen, T. T., Mizielinska, S., Holmes, H., Powell, N., Norona, F., Overgaard Larsen, J., Milioto, C., Wilson, K. M., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx003 · Cited by 32
“In addition, mutations in the microglial gene TREM2 have been identified in FTD cases (57) and cause altered microglial function (58).”
BackgroundFernández, M. V., Budde, J., Del‐Aguila, J. L., Ibáñez, L., Deming, Y. K., Harari, O., Norton, J. B., Morris, J. C., Goate, A., NIA-LOAD family study group, et al. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00209 · Cited by 30
Peng, G., Qiu, J., Liu, H., Zhou, M., Huang, S., Guo, W., Lin, Y., Chen, X. '., Li, Z., Li, G., et al. (2019) · Journal of Molecular Neuroscience · doi:10.1007/s12031-019-01424-7 · Cited by 30
Shen, T. S., Lee, A., Shen, C., & Lin, C. J. (2015) · Genetics Research · doi:10.1017/s0016672315000166 · Cited by 27
Kiianitsa, K., Kurtz, I., Beeman, N. E., Matsushita, M. M., Chien, W., Raskind, W. H., & Korvatska, O. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.2hi0720-463rr · Cited by 25
Duran-Aniotz, C. A., Orellana, P., Rodríguez, T. L., Henríquez, F., Cabello, V., Aguirre-Pinto, M. F., Escobedo, T., Takada, L. T., Piña‐Escudero, S. D., López, O. L., et al. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.663407 · Cited by 27
“These mutations of TREM2 have also been associated with FTD-like presentations without bone involvement (95, 96).”
BackgroundUmoh, I. O., Reis, H. J., & de Oliveira, A. C. P. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25053044 · Cited by 28
ADNI, Nho, K. T., Horgusluoglu, E., Kim, S., Risacher, S. L., Kim, D., Foroud, T., Aisen, P. S. S., Petersen, R. C., Jack, C. R., et al. (2016) · BMC Medical Genomics · doi:10.1186/s12920-016-0190-9 · Cited by 26
“Several sequencing-based association studies could identify functional risk variants with large effects on LOAD pathogenesis within TREM2, ABCA7, and PLD3 genes [7–11].”
BackgroundIntracellular trafficking of TREM2 is regulated by presenilin 1
Zhao, Y., Li, X., Huang, T. Y., Jiang, L.-L., Tan, Z., Zhang, M., Cheng, I. H.-J., Wang, X., Bu, G., Zhang, Y., et al. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.200 · Cited by 26
Therapeutic and diagnostic challenges for frontotemporal dementia
Dâ€TMAlton, S., & Lewis, J. M. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00204 · Cited by 26
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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