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Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

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 microtu... Full description

Journal Title: Nature 2006-08-24, Vol.442 (7105), p.916-919
Main Author: Mackenzie, Ian R
Other Authors: Hutton, Mike , Baker, Matt , Pickering-Brown, Stuart M , Gass, Jennifer , Rademakers, Rosa , Lindholm, Caroline , Snowden, Julie , Adamson, Jennifer , Sadovnick, A. Dessa , Rollinson, Sara , Cannon, Ashley , Dwosh, Emily , Neary, David , Melquist, Stacey , Richardson, Anna , Dickson, Dennis , Berger, Zdenek , Eriksen, Jason , Robinson, Todd , Zehr, Cynthia , Dickey, Chad A , Crook, Richard , McGowan, Eileen , Mann, David , Boeve, Bradley , Feldman, Howard
Format: Electronic Article Electronic Article
Language: English
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Publisher: London: Nature Publishing
ID: ISSN: 0028-0836
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title: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
format: Article
creator:
  • Mackenzie, Ian R
  • Hutton, Mike
  • Baker, Matt
  • Pickering-Brown, Stuart M
  • Gass, Jennifer
  • Rademakers, Rosa
  • Lindholm, Caroline
  • Snowden, Julie
  • Adamson, Jennifer
  • Sadovnick, A. Dessa
  • Rollinson, Sara
  • Cannon, Ashley
  • Dwosh, Emily
  • Neary, David
  • Melquist, Stacey
  • Richardson, Anna
  • Dickson, Dennis
  • Berger, Zdenek
  • Eriksen, Jason
  • Robinson, Todd
  • Zehr, Cynthia
  • Dickey, Chad A
  • Crook, Richard
  • McGowan, Eileen
  • Mann, David
  • Boeve, Bradley
  • Feldman, Howard
subjects:
  • Biological and medical sciences
  • Cell Survival
  • Chromosomes, Human, Pair 17 - genetics
  • Codon, Terminator - genetics
  • Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
  • Dementia - genetics
  • Dementia - physiopathology
  • Frontal Lobe - metabolism
  • Frontal Lobe - physiopathology
  • Genetic Linkage - genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins - genetics
  • Intercellular Signaling Peptides and Proteins - metabolism
  • Medical sciences
  • Mutation - genetics
  • Neurology
  • Neurons - metabolism
  • Neurons - pathology
  • Physical Chromosome Mapping
  • Progranulins
  • Protein Precursors - genetics
  • Protein Precursors - metabolism
  • RNA Stability
  • RNA, Messenger - genetics
  • RNA, Messenger - metabolism
  • tau Proteins - deficiency
  • tau Proteins - genetics
  • Temporal Lobe - metabolism
  • Temporal Lobe - physiopathology
ispartof: Nature, 2006-08-24, Vol.442 (7105), p.916-919
description: 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.
language: eng
source:
identifier: ISSN: 0028-0836
fulltext: no_fulltext
issn:
  • 0028-0836
  • 1476-4687
  • 1476-4679
url: Link


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titleMutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
creatorMackenzie, Ian R ; Hutton, Mike ; Baker, Matt ; Pickering-Brown, Stuart M ; Gass, Jennifer ; Rademakers, Rosa ; Lindholm, Caroline ; Snowden, Julie ; Adamson, Jennifer ; Sadovnick, A. Dessa ; Rollinson, Sara ; Cannon, Ashley ; Dwosh, Emily ; Neary, David ; Melquist, Stacey ; Richardson, Anna ; Dickson, Dennis ; Berger, Zdenek ; Eriksen, Jason ; Robinson, Todd ; Zehr, Cynthia ; Dickey, Chad A ; Crook, Richard ; McGowan, Eileen ; Mann, David ; Boeve, Bradley ; Feldman, Howard
creatorcontribMackenzie, Ian R ; Hutton, Mike ; Baker, Matt ; Pickering-Brown, Stuart M ; Gass, Jennifer ; Rademakers, Rosa ; Lindholm, Caroline ; Snowden, Julie ; Adamson, Jennifer ; Sadovnick, A. Dessa ; Rollinson, Sara ; Cannon, Ashley ; Dwosh, Emily ; Neary, David ; Melquist, Stacey ; Richardson, Anna ; Dickson, Dennis ; Berger, Zdenek ; Eriksen, Jason ; Robinson, Todd ; Zehr, Cynthia ; Dickey, Chad A ; Crook, Richard ; McGowan, Eileen ; Mann, David ; Boeve, Bradley ; Feldman, Howard
descriptionFrontotemporal 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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subjectBiological and medical sciences ; Cell Survival ; Chromosomes, Human, Pair 17 - genetics ; Codon, Terminator - genetics ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Dementia - genetics ; Dementia - physiopathology ; Frontal Lobe - metabolism ; Frontal Lobe - physiopathology ; Genetic Linkage - genetics ; Humans ; Intercellular Signaling Peptides and Proteins - genetics ; Intercellular Signaling Peptides and Proteins - metabolism ; Medical sciences ; Mutation - genetics ; Neurology ; Neurons - metabolism ; Neurons - pathology ; Physical Chromosome Mapping ; Progranulins ; Protein Precursors - genetics ; Protein Precursors - metabolism ; RNA Stability ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; tau Proteins - deficiency ; tau Proteins - genetics ; Temporal Lobe - metabolism ; Temporal Lobe - physiopathology
ispartofNature, 2006-08-24, Vol.442 (7105), p.916-919
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1Hutton, Mike
2Baker, Matt
3Pickering-Brown, Stuart M
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5Rademakers, Rosa
6Lindholm, Caroline
7Snowden, Julie
8Adamson, Jennifer
9Sadovnick, A. Dessa
10Rollinson, Sara
11Cannon, Ashley
12Dwosh, Emily
13Neary, David
14Melquist, Stacey
15Richardson, Anna
16Dickson, Dennis
17Berger, Zdenek
18Eriksen, Jason
19Robinson, Todd
20Zehr, Cynthia
21Dickey, Chad A
22Crook, Richard
23McGowan, Eileen
24Mann, David
25Boeve, Bradley
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title
0Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
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descriptionFrontotemporal 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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1Cell Survival
2Chromosomes, Human, Pair 17 - genetics
3Codon, Terminator - genetics
4Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
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6Dementia - physiopathology
7Frontal Lobe - metabolism
8Frontal Lobe - physiopathology
9Genetic Linkage - genetics
10Humans
11Intercellular Signaling Peptides and Proteins - genetics
12Intercellular Signaling Peptides and Proteins - metabolism
13Medical sciences
14Mutation - genetics
15Neurology
16Neurons - metabolism
17Neurons - pathology
18Physical Chromosome Mapping
19Progranulins
20Protein Precursors - genetics
21Protein Precursors - metabolism
22RNA Stability
23RNA, Messenger - genetics
24RNA, Messenger - metabolism
25tau Proteins - deficiency
26tau Proteins - genetics
27Temporal Lobe - metabolism
28Temporal Lobe - physiopathology
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titleMutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
authorMackenzie, Ian R ; Hutton, Mike ; Baker, Matt ; Pickering-Brown, Stuart M ; Gass, Jennifer ; Rademakers, Rosa ; Lindholm, Caroline ; Snowden, Julie ; Adamson, Jennifer ; Sadovnick, A. Dessa ; Rollinson, Sara ; Cannon, Ashley ; Dwosh, Emily ; Neary, David ; Melquist, Stacey ; Richardson, Anna ; Dickson, Dennis ; Berger, Zdenek ; Eriksen, Jason ; Robinson, Todd ; Zehr, Cynthia ; Dickey, Chad A ; Crook, Richard ; McGowan, Eileen ; Mann, David ; Boeve, Bradley ; Feldman, Howard
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5Dementia - genetics
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7Frontal Lobe - metabolism
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27Temporal Lobe - metabolism
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9Sadovnick, A. Dessa
10Rollinson, Sara
11Cannon, Ashley
12Dwosh, Emily
13Neary, David
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17Berger, Zdenek
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abstractFrontotemporal 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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