Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval

Rademakers, R; Cruts, Marc; Dermaut, Bart; Sleegers, Kristel; Rosso, SM; Broeck, Marleen Van den; Backhovens, Hubert; Swieten, John van; Duijn, CM van; Broeckhoven, Christine Van

doi:10.1038/sj.mp.4001198

Cited by 102 publications

(84 citation statements)

References 44 publications

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“…In addition, mild parkinsonian features are frequent but motor neuron disease was remarkably rare Josephs et al, 2007;Mackenzie, 2007]. Furthermore, other neurodegenerative brain diseases including corticobasal syndrome (CBS) [Masellis et al, 2006;Benussi et al, 2008;Rademakers et al, 2007;Le Ber et al, 2007;Lopez de Munain et al, 2008;Spina et al, 2007b;Le Ber et al, 2008], AD [van Duijn et al, 1994;Rademakers et al, 2002;Brouwers et al, 2007;Rademakers et al, 2007] and PD [Brouwers et al, 2007] were also linked with GRN mutations. However, compared to variants with unclear pathogenic significance, GRN null mutations were not frequently found in patients with a disease other than FTLD Schymick et al, 2007;Brouwers et al, 2007;Sleegers et al, in press;Pickering-Brown et al, 2008].…”

Section: Clinical Biological and Diagnostic Significance Genotype-pmentioning

confidence: 99%

“…Initially, GRN mutations were identified in the three most significantly linked FTLDU-17 families: Dutch 1083, Belgian DR8, and Canadian UBC-17 (Table 1) [Rademakers et al, 2002;van der Zee et al, 2006;Cruts et al, 2006;Baker et al, 2006;Mackenzie et al, 2006b]. In Family 1083 the disease segregated with a nonsense mutation at codon 125 (p.Q125X) and in Family UBC-17 with a 4-basepair (bp) insertion resulting in a frameshift (p.C31LfsX35) Baker et al, 2006].…”

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

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Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

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Section: Clinical Biological and Diagnostic Significance Genotype-pmentioning

confidence: 99%

Section: Grn Mutation Spectrum Null Mutationsmentioning

confidence: 99%

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

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“…Subsequently, many familial cases of frontotemporal dementia with parkinsonism were linked to chromosome 17 (FTDP-17) (Foster et al 1997). Some were associated with mutations in the microtubule associated protein tau (MAPT), (Hutton et al 1998;Ingram and Spillantini 2002) while others were not (Kertesz et al 2000;Rademakers et al 2002;Mackenzie et al 2006b). Many cases of FTDP-17 did not exhibit immunostaining for tau on pathologic examination (Kertesz et al 2000;Rosso et al 2001;Savioz et al 2003;Mackenzie et al 2006b;van der Zee et al 2006), and mutations in MAPT were absent in all of these.…”

Section: Introductionmentioning

confidence: 99%

Prominent phenotypic variability associated with mutations in Progranulin

Kelley

Haidar

Boeve

et al. 2009

Neurobiology of Aging

162

141

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Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied

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“…Genetic linkage led to the identification of more than 40 different mutations in the microtubule-associated protein tau gene locus on chromosome 17 (4). However, a number of familial FTLD cases failed to exhibit mutations in the tau gene, although strong linkage to chromosome 17 was observed (5). These cases were characterized by tau-and ␣-synuclein-negative, ubiquitin-positive cytoplasmic and intranuclear inclusions (3).…”

mentioning

confidence: 99%

Missense Mutations in the Progranulin Gene Linked to Frontotemporal Lobar Degeneration with Ubiquitin-immunoreactive Inclusions Reduce Progranulin Production and Secretion

Shankaran

Capell

Hruscha

et al. 2008

Journal of Biological Chemistry

159

132

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Loss of function mutations in progranulin cause tau-negative frontotemporal lobar degeneration with ubiquitin-positive inclusions. A major protein component of these inclusions is TDP-43, which becomes hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments, which apparently translocate from nuclei to the cytoplasm. Most progranulin mutations are nonsense mutations resulting in nonsensemediated mRNA decay and consequently reduced progranulin protein levels. However, some missense mutations are described that occur within the signal sequence and mature progranulin. We now demonstrate that a progranulin mutation located within the signal sequence (PGRN A9D) results in cytoplasmic missorting with extremely low expression. In contrast, two other progranulin mutations (PGRN P248L and R432C) are expressed as immature proteins but are inefficiently transported through and partially degraded within the secretory pathway, resulting in a significantly reduced secretion. Thus apparently all progranulin mutations cause reduced protein expression or secretion, although by different cellular mechanisms. To investigate a putative relationship between reduced expression of progranulin and TDP-43 relocalization and deposition, we down-regulated progranulin in human cell lines and in zebrafish. Upon reduction of progranulin, neither a major redistribution of TDP-43 nor proteolytic processing to disease-characterizing C-terminal fragments could be observed.Dementias are a major health problem in our aging society. The most frequent forms of dementia, namely Alzheimer disease, frontotemporal lobar degeneration (FTLD), 3 as well as dementia with Lewy bodies and related disorders are associated with selective neuronal cell loss. In these neurodegenerative disorders, proteins, which are normally soluble are known to misfold because of proteolytic processing and/or abnormal posttranslational modifications. Such insoluble amyloidogenic proteins are often deposited and may form reservoirs for neurotoxic oligomers (1). FTLD, which accounts approximately for 15% of all dementias, is characterized by two different types of cellular inclusions. About 40% of FTLD cases have tau-positive inclusions (2, 3). Genetic linkage led to the identification of more than 40 different mutations in the microtubule-associated protein tau gene locus on chromosome 17 (4). However, a number of familial FTLD cases failed to exhibit mutations in the tau gene, although strong linkage to chromosome 17 was observed (5). These cases were characterized by tau-and ␣-synuclein-negative, ubiquitin-positive cytoplasmic and intranuclear inclusions (3). The inclusions are observed in the frontotemporal cortex, the temporal neocortex, and the hippocampus and define the frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (FTLD-U). FTLD-U is the most frequent neuropathological form of FTLD and presents with progressive social, behavioral symptoms, and language dysfunction. Patients may also develop typical symptoms of motoneuron...

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Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval

Cited by 102 publications

References 44 publications

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

Prominent phenotypic variability associated with mutations in Progranulin

Missense Mutations in the Progranulin Gene Linked to Frontotemporal Lobar Degeneration with Ubiquitin-immunoreactive Inclusions Reduce Progranulin Production and Secretion

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