 |
|
The Spectrum of Mutations in ProgranulinA Collaborative Study Screening 545 Cases of Neurodegeneration
Chang-En Yu, PhD;
Thomas D. Bird, MD;
Lynn M. Bekris, PhD;
Thomas J. Montine, MD, PhD;
James B. Leverenz, MD;
Ellen Steinbart, MA;
Nichole M. Galloway, BS;
Howard Feldman, MD;
Randall Woltjer, MD;
Carol A. Miller, MD;
Elisabeth McCarty Wood, MS;
Murray Grossman, MD;
Leo McCluskey, MD, MBE;
Christopher M. Clark, MD;
Manuela Neumann, MD;
Adrian Danek, MD;
Douglas R. Galasko, MD;
Steven E. Arnold, MD;
Alice Chen-Plotkin, MD;
Anna Karydas, BA;
Bruce L. Miller, MD;
John Q. Trojanowski, MD, PhD;
Virginia M.-Y. Lee, PhD;
Gerard D. Schellenberg, PhD;
Vivianna M. Van Deerlin, MD, PhD
Arch Neurol. 2010;67(2):161-170.
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.
Author Affiliations: Geriatric (Drs Yu, Bird, and Bekris and Mss Steinbart and Galloway) and Mental Illness (Dr Leverenz) Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington; Divisions of Gerontology and Geriatric Medicine (Drs Yu and Bekris), Medical Genetics (Dr Bird), Neurology (Drs Bird and Leverenz and Ms Steinbart), and Pathology (Dr Montine), Department of Medicine, University of Washington School of Medicine, Seattle; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada (Dr Feldman); Department of Neuropathology, Oregon Health & Science University, Portland (Dr Woltjer); Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles (Dr C. A. Miller); Center for Neurodegenerative Disease Research (Ms Wood and Drs Chen-Plotkin, Trojanowski, Lee, and Van Deerlin), Departments of Pathology and Laboratory Medicine (Drs Trojanowski, Lee, Schellenberg, and Van Deerlin), Neurology (Drs Grossman, McCluskey, Clark, Arnold, and Chen-Plotkin), and Psychiatry (Dr Arnold) and Institute on Aging (Drs Clark, Arnold, Trojanowski, Lee, Schellenberg, and Van Deerlin), University of Pennsylvania School of Medicine, Philadelphia; Center for Neuropathology and Prion Research (Dr Neumann) and Neurologische Klinik (Dr Danek), Ludwig-Maximilians-Universität, Munich, Germany; Department of Neuroscience, University of California at San Diego and Veterans Affairs Medical Center, San Diego; (Dr Galasko); and Memory and Aging Center, Department of Neurology, University of California at San Francisco (Ms Karydas and Dr B. L. Miller).
 CiteULike  Connotea  Delicious  Digg  Facebook  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLES
This Month in Archives of Neurology
Arch Neurol. 2010;67(2):143-144.
FULL TEXT
Progress on Progranulin
Bradley F. Boeve
Arch Neurol. 2010;67(2):145-147.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Frontotemporal Dementia: Implications for Understanding Alzheimer Disease
Goedert et al.
Cold Spring Harb Perspect Med 2012;2:a006254-a006254.
ABSTRACT
| FULL TEXT
Sporadic Corticobasal Syndrome With Progranulin Mutation Presenting as Progressive Apraxic Agraphia
Passov et al.
Arch Neurol 2011;68:376-380.
ABSTRACT
| FULL TEXT
An algorithm for genetic testing of frontotemporal lobar degeneration
Goldman et al.
Neurology 2011;76:475-483.
ABSTRACT
| FULL TEXT
Genetic Causes of Frontotemporal Degeneration
See et al.
J Geriatr Psychiatry Neurol 2010;23:260-268.
ABSTRACT
Pathological 43-kDa Transactivation Response DNA-Binding Protein in Older Adults With and Without Severe Mental Illness
Geser et al.
Arch Neurol 2010;67:1238-1250.
ABSTRACT
| FULL TEXT
A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition
Garbern et al.
Brain 2010;133:1391-1402.
ABSTRACT
| FULL TEXT
Progress on Progranulin
Boeve
Arch Neurol 2010;67:145-147.
FULL TEXT
|
