Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia-like Syndrome Without Bone Involvement

JAMA neurology 01/2013; 70(1):78-84. DOI: 10.1001/jamaneurol.2013.579
Source: PubMed


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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    • "Recent genetic studies suggest that triggering receptor expressed on myeloid cells 2 (TREM2) gene may be associated with the susceptibility of AD because a low-frequency variant R47H increases the risk of this disease by nearly 3-fold in Caucasian populations (Guerreiro et al., 2013a; Jonsson et al., 2013). Interestingly, loss-of-function mutations in TREM2 gene are also related with the clinical phenotypes and neuropathology of FTD, supporting the contribution of TREM2 to the pathogenesis and progression of this disorder (Guerreiro et al., 2013b; Rayaprolu et al., 2013). TREM2 is a 230 amino acid type I transmembrane receptor that belongs to the superfamily of immunoglobulin (Colonna, 2003). "
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    ABSTRACT: Tau pathology is a pathological hallmark for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. As a novel susceptibility gene for these 2 diseases, triggering receptor expressed on myeloid cells 2 (TREM2) gene encodes an immune receptor that is uniquely expressed by microglia. Recently, a correlation between TREM2 expression and hyperphosphorylated tau has been revealed in the brain of Alzheimer's disease patients, suggesting a potential association between TREM2 and tau pathology. However, the role of TREM2 in tau pathology remains unclear thus far. Herein, using P301S mice, we showed that TREM2 was upregulated in microglia during disease progression. Silencing of brain TREM2 exacerbated tau pathology in P301S mice. This exacerbation might be attributed to neuroinflammation-induced hyperactivation of tau kinases. Additionally, more severe neurodegenerative changes and spatial learning deficits were observed following TREM2 silencing. Our results imply that TREM2 attenuates tau kinase activity through restriction of neuroinflammation, and thus protects against tau pathology. These findings further suggest that TREM2 may represent as a potential therapeutic target for tau-related neurodegenerative diseases.
    Neurobiology of aging 09/2015; DOI:10.1016/j.neurobiolaging.2015.08.019 · 5.01 Impact Factor
    • "c o m / l o ca t e / n e u a g i n g early-onset neurodegeneration (Paloneva et al., 2002; Sorgana et al., 2003). Risk for other neurodegenerative diseases, including frontotemporal dementia (Cuyvers et al., 2014, Guerreiro et al., 2013b, 2013c; Rayaprolu, 2013), Parkinson's disease (Rayaprolu et al., 2013), and sporadic amyotrophic lateral sclerosis (Cady et al., 2014), also appears to be mediated by TREM2 variation. Network analysis revealed connections of other known AD genes to TREM2, as well as genes with known functions in other neurological diseases, suggesting a microglial link among these diseases (Forabosco et al., 2013). "
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    ABSTRACT: Over 20 risk loci have been identified for late-onset Alzheimer's disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here, we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (odds ratio = 7.40, p = 3.66E-06). In addition to Alzheimer's disease risk, we also examined the association of R47H with Alzheimer's disease-related phenotypes, including age-at-onset, psychosis, and amyloid deposition but found no significant association. Our results corroborate those of other studies implicating TREM2 as an LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 04/2015; 36(8). DOI:10.1016/j.neurobiolaging.2015.04.012 · 5.01 Impact Factor
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    • "leukoencephalopathy (Paloneva et al., 2002). In the case of p.T66M, this variant was identified in a homozygous state in a Turkish patient presenting clinically with an FTD-like syndrome without bone involvement (Guerreiro et al., 2013b). In the present cohort, both variants were found each in a single subject with bv-FTD, suggesting that p.W44X and p.T66M may also contribute to the etiology of FTD-S. "
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    ABSTRACT: Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.
    Neurobiology of Aging 12/2014; 35(11). DOI:10.1016/j.neurobiolaging.2014.06.018. · 5.01 Impact Factor
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