The spectrum of mutations in progranulin: A collaborative study screening 545 cases of neurodegeneration

Chang En Yu, Thomas D. Bird, Lynn M. Bekris, Thomas J. Montine, James B. Leverenz, Ellen Steinbart, Nichole M. Galloway, Howard Feldman, Randall (Randy) Woltjer, Carol A. Miller, Elisabeth McCarty Wood, Murray Grossman, Leo McCluskey, Christopher M. Clark, Manuela Neumann, Adrian Danek, Douglas R. Galasko, Steven E. Arnold, Alice Chen-Plotkin, Anna KarydasBruce L. Miller, John Q. Trojanowski, Virginia M Y Lee, Gerard D. Schellenberg, Vivianna M. Van Deerlin

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Background: Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations. Objectives: To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants. Design: Case-control study. Setting: Clinical and neuropathology dementia research studies at 8 academic centers. Participants: Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/ motor neuron disease, corticobasal syndrome/ corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease. Main Outcome Measures: Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays. Results: We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history. Conclusions: Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.

Original languageEnglish (US)
Pages (from-to)161-170
Number of pages10
JournalArchives of Neurology
Volume67
Issue number2
DOIs
StatePublished - Feb 2010

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Frontotemporal Dementia
Mutation
Dementia
Neurodegenerative Diseases
Amyotrophic Lateral Sclerosis
Screening
Primary Progressive Aphasia
Guam
Pick Disease of the Brain
Progressive Supranuclear Palsy
Multiple System Atrophy
Haploinsufficiency
Motor Neuron Disease
Mutation Rate
Base Pairing
Computer Simulation
Introns
Case-Control Studies
Exons

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Yu, C. E., Bird, T. D., Bekris, L. M., Montine, T. J., Leverenz, J. B., Steinbart, E., ... Van Deerlin, V. M. (2010). The spectrum of mutations in progranulin: A collaborative study screening 545 cases of neurodegeneration. Archives of Neurology, 67(2), 161-170. https://doi.org/10.1001/archneurol.2009.328

The spectrum of mutations in progranulin : A collaborative study screening 545 cases of neurodegeneration. / Yu, Chang En; Bird, Thomas D.; Bekris, Lynn M.; Montine, Thomas J.; Leverenz, James B.; Steinbart, Ellen; Galloway, Nichole M.; Feldman, Howard; Woltjer, Randall (Randy); Miller, Carol A.; Wood, Elisabeth McCarty; Grossman, Murray; McCluskey, Leo; Clark, Christopher M.; Neumann, Manuela; Danek, Adrian; Galasko, Douglas R.; Arnold, Steven E.; Chen-Plotkin, Alice; Karydas, Anna; Miller, Bruce L.; Trojanowski, John Q.; Lee, Virginia M Y; Schellenberg, Gerard D.; Van Deerlin, Vivianna M.

In: Archives of Neurology, Vol. 67, No. 2, 02.2010, p. 161-170.

Research output: Contribution to journalArticle

Yu, CE, Bird, TD, Bekris, LM, Montine, TJ, Leverenz, JB, Steinbart, E, Galloway, NM, Feldman, H, Woltjer, RR, Miller, CA, Wood, EM, Grossman, M, McCluskey, L, Clark, CM, Neumann, M, Danek, A, Galasko, DR, Arnold, SE, Chen-Plotkin, A, Karydas, A, Miller, BL, Trojanowski, JQ, Lee, VMY, Schellenberg, GD & Van Deerlin, VM 2010, 'The spectrum of mutations in progranulin: A collaborative study screening 545 cases of neurodegeneration', Archives of Neurology, vol. 67, no. 2, pp. 161-170. https://doi.org/10.1001/archneurol.2009.328
Yu, Chang En ; Bird, Thomas D. ; Bekris, Lynn M. ; Montine, Thomas J. ; Leverenz, James B. ; Steinbart, Ellen ; Galloway, Nichole M. ; Feldman, Howard ; Woltjer, Randall (Randy) ; Miller, Carol A. ; Wood, Elisabeth McCarty ; Grossman, Murray ; McCluskey, Leo ; Clark, Christopher M. ; Neumann, Manuela ; Danek, Adrian ; Galasko, Douglas R. ; Arnold, Steven E. ; Chen-Plotkin, Alice ; Karydas, Anna ; Miller, Bruce L. ; Trojanowski, John Q. ; Lee, Virginia M Y ; Schellenberg, Gerard D. ; Van Deerlin, Vivianna M. / The spectrum of mutations in progranulin : A collaborative study screening 545 cases of neurodegeneration. In: Archives of Neurology. 2010 ; Vol. 67, No. 2. pp. 161-170.
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abstract = "Background: Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations. Objectives: To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants. Design: Case-control study. Setting: Clinical and neuropathology dementia research studies at 8 academic centers. Participants: Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/ motor neuron disease, corticobasal syndrome/ corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease. Main Outcome Measures: Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays. Results: We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9{\%} (30 of 434) of all FTD-spectrum cases, 21.4{\%} (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0{\%} (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2{\%} (9 of 16) of cases of FTLD-U with a family history. Conclusions: Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.",
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T1 - The spectrum of mutations in progranulin

T2 - A collaborative study screening 545 cases of neurodegeneration

AU - Yu, Chang En

AU - Bird, Thomas D.

AU - Bekris, Lynn M.

AU - Montine, Thomas J.

AU - Leverenz, James B.

AU - Steinbart, Ellen

AU - Galloway, Nichole M.

AU - Feldman, Howard

AU - Woltjer, Randall (Randy)

AU - Miller, Carol A.

AU - Wood, Elisabeth McCarty

AU - Grossman, Murray

AU - McCluskey, Leo

AU - Clark, Christopher M.

AU - Neumann, Manuela

AU - Danek, Adrian

AU - Galasko, Douglas R.

AU - Arnold, Steven E.

AU - Chen-Plotkin, Alice

AU - Karydas, Anna

AU - Miller, Bruce L.

AU - Trojanowski, John Q.

AU - Lee, Virginia M Y

AU - Schellenberg, Gerard D.

AU - Van Deerlin, Vivianna M.

PY - 2010/2

Y1 - 2010/2

N2 - Background: Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations. Objectives: To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants. Design: Case-control study. Setting: Clinical and neuropathology dementia research studies at 8 academic centers. Participants: Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/ motor neuron disease, corticobasal syndrome/ corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease. Main Outcome Measures: Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays. Results: We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history. Conclusions: Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.

AB - Background: Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations. Objectives: To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants. Design: Case-control study. Setting: Clinical and neuropathology dementia research studies at 8 academic centers. Participants: Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/ motor neuron disease, corticobasal syndrome/ corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease. Main Outcome Measures: Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays. Results: We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history. Conclusions: Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.

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