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Mutations in Progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature

Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
Nature (Impact Factor: 42.35). 09/2006; 442(7105):916-9. DOI: 10.1038/nature05016
Source: PubMed

ABSTRACT Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.

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    • "Frontotemporal dementia (FTD) accounts for $50% of dementia cases before the age of 60. Up to 40% of FTD patients have a familial history (Goldman et al., 2005; van Swieten and Heutink, 2008) due to mutations in the microtubule-associated protein tau gene (MAPT), progranulin gene (GRN), or C9orf72 gene (Baker et al., 2006; Cruts et al., 2006; DeJesus-Hernandez et al., 2011; Hutton et al., 1998; Renton et al., 2011). The majority of FTD-causing mutations in GRN are predicted to result in functional null alleles, causing haploinsufficiency. "
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    ABSTRACT: Frontotemporal dementia (FTD) accounts for ∼50% of dementia cases before the age of 60. Up to 40% of FTD patients have a familial history (Goldman et al., 2005 and van Swieten and Heutink, 2008) due to mutations in the microtubule-associated protein tau gene (MAPT), progranulin gene (GRN), or C9orf72 gene (Baker et al., 2006, Cruts et al., 2006, DeJesus-Hernandez et al., 2011, Hutton et al., 1998 and Renton et al., 2011). The majority of FTD-causing mutations in GRN are predicted to result in functional null alleles, causing haploinsufficiency. Progranulin (PGRN) has neurotrophic function in vitro and in vivo. Although PGRN−/− mice are viable, they do not recapitulate all the features of FTD (Kayasuga et al., 2007).
    Stem Cell Reports 12/2014; 2(1). DOI:10.1016/j.stemcr.2014.12.001 · 5.64 Impact Factor
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    • "Within the reported GRN mutation carriers with clinical phenotype of PPA [6] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22], the prevalent clinical presentation is the non fluent variant. Only a few single cases with semantic disorders have been reported in association with GRN mutations [24]. "
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    ABSTRACT: Progranulin (GRN) mutations are typically associated with the behavioral variant of frontotemporal dementia and the non-fluent variant of primary progressive aphasia phenotypes. Hereby, we describe a patient affected by semantic variant of primary progressive aphasia (svPPA) with a highly positive family history of dementia, carrying a novel GRN missense variation in exon 11 [g.2897 C > T (p.Thr409Met)], predicted in silico to be damaging to protein structure and function. The variant was absent in 175 frontotemporal lobar degeneration (FTLD) patients and in 38 healthy subjects. This case confirms that GRN represents one of the most frequent FTLD genetic causes, suggesting that a screening is indicated in the case of svPPA presentation.
    Journal of Alzheimer's disease: JAD 04/2013; 36(3). DOI:10.3233/JAD-130317 · 4.15 Impact Factor
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    • "Neuropathological classification of FTLD-tau and FTLD-TDP subtypes (PSP, progressive supranuclear palsy; CBD, corticobasal degeneration; PiD, Pick's disease; FTDP17, frontotemporal dementia with Parkinsonism linked to chromosome 17; Tauopathy NOS, unclassifiable tauopathy; Subtypes A–D, morphological subtypes of FTLD-TDP; ALS-FTLD, amyotrophic lateral sclerosis with FTLD-TDP; FTLD-FUS, FTLD with fused in sarcoma protein inclusions; FTLD-UPS, FTLD with tau-and TDP-43-negative ubiquitinated inclusions; FTLD-ni, FTLD in the absence of significant neuropathological inclusions), (B) pathogenic mutation associations with underlying neuropathology (dashed-line separates less common molecular etiologies of FTLD; MAPT, tau resulting in FTDP-17; C90rf72, pathogenic hexanucleotide expansion resulting in FTLD and/or ALS associated with FTLD-TDP B; GRN, progranulin resulting in FTLD-TDP type A; TARDP, TDP-43 resulting in ALS ± FTLD and less commonly FTLD; VCP, valosin-containing protein resulting in inclusion body myopathy with Paget's disease of bone and frontotemporal dementia with FTLD-TDP subtype D; FUS, fused-in sarcoma protein resulting in FTLD-FUS; and CHMP2B, charged mutlivesciular body protein 2B resulting in FTLD-UPS), (C) clinicopathological correlations of FTLD (colored regions of clinical syndromes represent relative percentages of neuropathological subtypes found in autopsy studies; AD, Alzheimer's disease; bvFTD, behavioral variant of FTLD; PPA, primary progressive aphasia; svPPA, semantic variant PPA; naPPA, nonfluent agrammatic variant PPA; lvPPA, logopenic variant PPA; +ALS, co-morbid amyotrophic lateral sclerosis; +EPS, co-morbid extra-pyramidal Parkinsonian symptoms: i.e., features of akinetic-rigid syndromes of PSP or corticobasal syndrome). genetic etiologies resulting in FTLD are exclusively associated with specific underlying neuropathologies (Figure 1B), despite heterogeneous expression of FTLD clinical syndromes, and include pathogenic mutations in the gene for progranulin (GRN) (Baker et al., 2006; Cruts et al., 2006), tau (MAPT) (Hutton et al., 1998), and C9orf72 (C9orf72) (Dejesus-Hernandez et al., 2011; Renton et al., 2011). Less common genetic etiologies of FTLD include: valosin-containing protein (VCP) resulting in inclusion body myopathy with Paget's disease of bone and frontotemporal dementia with FTLD-TDP subtype D neuropathology, TARDBP coding for TDP-43 protein and causing ALS or ALS-FTLD (rarely FTLD-TDP alone), CHMP2B coding for charged mutlivesciular body protein 2B and resulting in FTLD-UPS, and mutations in FUS causing FTLD-FUS (Figure 1B) (Mackenzie et al., 2010). "
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    ABSTRACT: Accurate ante mortem diagnosis in frontotemporal lobar degeneration (FTLD) is crucial to the development and implementation of etiology-based therapies. Several neurodegenerative disease-associated proteins, including the major protein constituents of inclusions in Alzheimer's disease (AD) associated with amyloid-beta (Aβ(1-42)) plaque and tau neurofibrillary tangle pathology, can be measured in cerebrospinal fluid (CSF) for diagnostic applications. Comparative studies using autopsy-confirmed samples suggest that CSF total-tau (t-tau) and Aβ(1-42) levels can accurately distinguish FTLD from AD, with a high t-tau to Aβ(1-42) ratio diagnostic of AD; however, there is also an urgent need for FTLD-specific biomarkers. These analytes will require validation in large autopsy-confirmed cohorts and face challenges of standardization of within- and between-laboratory sources of error. In addition, CSF biomarkers with prognostic utility and longitudinal study of CSF biomarker levels over the course of disease are also needed. Current goals in the field include identification of analytes that are easily and reliably measured and can be used alone or in a multi-modal approach to provide an accurate prediction of underlying neuropathology for use in clinical trials of disease modifying treatments in FTLD. To achieve these goals it will be of the utmost importance to view neurodegenerative disease, including FTLD, as a clinicopathological entity, rather than exclusively a clinical syndrome.
    Frontiers in Aging Neuroscience 02/2013; 5:6. DOI:10.3389/fnagi.2013.00006 · 2.84 Impact Factor
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