Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916-919

Department of Neuroscience, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
Nature (Impact Factor: 41.46). 09/2006; 442(7105):916-9. DOI: 10.1038/nature05016
Source: PubMed


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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Available from: Sara Rollinson, Oct 02, 2015
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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 · 5.37 Impact Factor
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    • "Genetic mutations clearly mirror the underpinnings of the disease, and give the opportunity to assess its pathogenetic and biological mechanism. Among others, GRN mutations are expected to induce a loss of 50% of progranulin, with a mechanism of haploinsufficiency, and the presence of ubiquitinated TDP-43 protein is the neuropathological hallmark [8], [20], [21]. The physiological role of progranulin, as well as the effect of its reduction in the brain, is still largely unknown, although it has been recently suggested that progranulin might be involved in inflammatory pathways and innate immunity [22], [23], and that it acts as a neurotrophic factor [24]. "
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    ABSTRACT: BackgroundMonogenic dementias represent a great opportunity to trace disease progression from preclinical to symptomatic stages. Frontotemporal Dementia related to Granulin (GRN) mutations presents a specific framework of brain damage, involving fronto-temporal regions and long inter-hemispheric white matter bundles. Multimodal resting-state functional MRI (rs-fMRI) is a promising tool to carefully describe disease signature from the earliest disease phase.ObjectiveTo define local connectivity alterations in GRN related pathology moving from the presymptomatic (asymptomatic GRN mutation carriers) to the clinical phase of the disease (GRN- related Frontotemporal Dementia).MethodsThirty-one GRN Thr272fs mutation carriers (14 patients with Frontotemporal Dementia and 17 asymptomatic carriers) and 38 healthy controls were recruited. Local connectivity measures (Regional Homogeneity (ReHo), Fractional Amplitude of Low Frequency Fluctuation (fALFF) and Degree Centrality (DC)) were computed, considering age and gender as nuisance variables as well as the influence of voxel-level gray matter atrophy.ResultsAsymptomatic GRN carriers had selective reduced ReHo in the left parietal region and increased ReHo in frontal regions compared to healthy controls. Considering Frontotemporal Dementia patients, all measures (ReHo, fALFF and DC) were reduced in inferior parietal, frontal lobes and posterior cingulate cortex. Considering GRN mutation carriers, an inverse correlation with age in the posterior cingulate cortex, inferior parietal lobule and orbitofrontal cortex was found.ConclusionsGRN pathology is characterized by functional brain network alterations even decades before the clinical onset; they involve the parietal region primarily and then spread to the anterior regions of the brain, supporting the concept of molecular nexopathies.
    PLoS ONE 09/2014; 9(9):e106500. DOI:10.1371/journal.pone.0106500 · 3.23 Impact Factor
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    • "This association is replicated in independent cohorts [2,3]. A number of previous studies showed that all GRN mutations cause FTLD-TDP by the mechanism of haploinsufficiency due to nonsense-mediated decay of mutated mRNAs [4,5]. A different study validated a substantial increase in TMEM106B mRNA and protein levels in FLTD-TDP brains with GRN mutations [6]. "
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    ABSTRACT: TMEM106B is a transmembrane glycoprotein of unknown function located within endosome/lysosome compartments expressed ubiquitously in various cell types. Previously, the genome-wide association study (GWAS) identified a significant association of TMEM106B single nucleotide polymorphisms (SNPs) with development of frontotemporal lobar degeneration with ubiquitinated TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP), particularly in the patients exhibiting the progranulin (PGRN) gene (GRN) mutations. Recent studies indicate that TMEM106B plays a pathological role in various neurodegenerative diseases, including Alzheimer's disease (AD). However, at present, the precise levels of TMEM106B expression in AD brains remain unknown. By quantitative reverse transcription (RT)-PCR (qPCR), western blot and immunohistochemistry, we studied TMEM106B and PGRN expression levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson's disease, multiple system atrophy and non-neurological cases. In AD brains, TMEM106B mRNA and protein levels were significantly reduced, whereas PGRN mRNA levels were elevated, compared with the levels in non-AD brains. In all brains, TMEM106B was expressed in the majority of cortical neurons, hippocampal neurons, and some populations of oligodendrocytes, reactive astrocytes and microglia with the location in the cytoplasm. In AD brains, surviving neurons expressed intense TMEM106B immunoreactivity, while senile plaques, neurofibrillary tangles and the perivascular neuropil, almost devoid of TMEM106B, intensely expressed PGRN. We found an inverse relationship between TMEM106B (downregulation) and PGRN (upregulation) expression levels in AD brains, suggesting a key role of TMEM106B in the pathological processes of AD.
    Alzheimer's Research and Therapy 03/2014; 6(2):17. DOI:10.1186/alzrt247 · 3.98 Impact Factor
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