Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

被引：86

作者：

Chen-Plotkin, Alice S. ^{[1
,2
]}

Martinez-Lage, Maria ^{[2
,5
]}

Sleiman, Patrick M. A. ^{[3
]}

Hu, William ^{[6
]}

Greene, Robert ^{[2
,4
]}

Wood, Elisabeth McCarty ^{[2
,4
]}

Bing, Shaoxu ^{[2
,4
]}

Grossman, Murray ^{[1
]}

Schellenberg, Gerard D.

Hatanpaa, Kimmo J. ^{[8
]}

Weiner, Myron F. ^{[9
,10
]}

White, Charles L., III ^{[8
]}

Brooks, William S. ^{[11
,12
]}

Halliday, Glenda M. ^{[11
,12
]}

Kril, Jillian J. ^{[13
,14
]}

Gearing, Marla ^{[7
]}

Beach, Thomas G. ^{[15
]}

Graff-Radford, Neill R. ^{[16
]}

Dickson, Dennis W. ^{[17
]}

Rademakers, Rosa ^{[17
]}

Boeve, Bradley F. ^{[18
]}

Pickering-Brown, Stuart M. ^{[19
]}

Snowden, Julie ^{[19
]}

van Swieten, John C. ^{[20
]}

Heutink, Peter ^{[21
]}

Seelaar, Harro ^{[20
]}

Murrell, Jill R. ^{[22
,23
]}

Ghetti, Bernardino ^{[22
,23
]}

Spina, Salvatore ^{[22
,23
,24
]}

Grafman, Jordan ^{[25
]}

Kaye, Jeffrey A. ^{[26
]}

Woltjer, Randall L. ^{[27
]}

Mesulam, Marsel ^{[28
]}

Bigio, Eileen ^{[28
]}

Llado, Albert ^{[29
]}

Miller, Bruce L. ^{[30
]}

Alzualde, Ainhoa ^{[31
]}

Moreno, Fermin ^{[32
]}

Rohrer, Jonathan D. ^{[33
]}

Mackenzie, Ian R. A. ^{[34
]}

Feldman, Howard H. ^{[35
,36
]}

Hamilton, Ronald L. ^{[37
]}

Cruts, Marc ^{[38
,39
]}

Engelborghs, Sebastiaan ^{[39
,40
,41
]}

De Deyn, Peter P. ^{[39
,40
,41
]}

Van Broeckhoven, Christine ^{[38
,39
]}

Bird, Thomas D. ^{[42
,43
,44
]}

Cairns, Nigel J. ^{[45
,46
]}

Goate, Allison ^{[46
]}

Frosch, Matthew P. ^{[47
,48
]}

机构：

[1] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA

[3] Univ Penn, Sch Med, Ctr Appl Genom, Div Human Genet,Dept Pediat, Philadelphia, PA 19104 USA

[4] Univ Penn, Sch Med, Inst Aging, Philadelphia, PA 19104 USA

[5] Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, E-08193 Barcelona, Spain

[6] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[7] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA

[8] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[9] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA

[10] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA

[11] Neurosci Res Australia, Sydney, NSW, Australia

[12] Univ New S Wales, Sydney, NSW, Australia

[13] Univ Sydney, Discipline Med, Sydney, NSW 2006, Australia

[14] Univ Sydney, Discipline Pathol, Sydney, NSW 2006, Australia

[15] Sun Hlth Res Inst, Sun City, AZ USA

[16] Mayo Sch Grad Med Educ, Coll Med, Dept Neurol, Jacksonville, FL USA

[17] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[18] Mayo Clin, Dept Neurol, Rochester, MN USA

[19] Univ Manchester, Neurodegenerat & Mental Hlth Res Grp, Manchester, Lancs, England

[20] Erasmus MC, Dept Neurol, Rotterdam, Netherlands

[21] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands

[22] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA

[23] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA

[24] Univ Siena, Dept Neurol Neurosurg & Behav Sci, I-53100 Siena, Italy

[25] Kessler Fdn Res Ctr, Traumat Brain Injury Res Lab, W Orange, NJ USA

[26] Oregon Hlth & Sci Univ, Dept Neurol & Biomed Engn, Portland, OR 97201 USA

[27] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA

[28] Northwestern Univ, Feinberg Sch Med, Alzheimer Dis Ctr, Chicago, IL 60611 USA

[29] ICN Hosp Clin Barcelona, Serv Neurol, Alzheimers Dis & Cognit Disorders Unit, Barcelona, Spain

[30] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[31] BioDonostia Inst, Ilundain Fdn, Neurosci Unit, San Sebastian, Spain

[32] BioDonostia Inst, Hosp Donostia, Neurol Serv, San Sebastian, Spain

[33] UCL Inst Neurol, Dementia Res Ctr, London, England

[34] Univ British Columbia, Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada

[35] Univ British Columbia, Div Neurol, Vancouver, BC V5Z 1M9, Canada

[36] Bristol Myers Squibb Co, Neurosci, Wallingford, CT 06492 USA

[37] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA

[38] VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, Belgium

[39] Univ Antwerp, Inst Born Bunge, B-2020 Antwerp, Belgium

[40] Hosp Network Antwerp ZNA & Middelheim, Dept Neurol, Antwerp, Belgium

[41] Memory Clin ZNA Hoge Beuken, Antwerp, Belgium

[42] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ Ctr, Seattle, WA USA

[43] Vet Affairs Puget Sound Hlth Care Syst, Ctr Clin, Seattle, WA USA

[44] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[45] Washington Univ, Sch Med, Alzheimers Dis Res Ctr, St Louis, MO USA

[46] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[47] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA

[48] Harvard Univ, Sch Med, Boston, MA USA

[49] Univ Wurzburg, Clin & Policlin Psychiat Psychosomat & Psychother, Wurzburg, Germany

[50] Karolinska Univ Hosp, Dept Geriatr Med, Stockholm, Sweden

来源：

ARCHIVES OF NEUROLOGY | 2011年 / 68卷 / 04期

基金：

英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会; 加拿大健康研究院;

关键词：

UBIQUITIN-POSITIVE INCLUSIONS; MUTATIONS; DEMENTIA; TAU; NEUROPATHOLOGY; VARIABILITY; PHENOTYPES; ALZHEIMER; VARIANTS; MISSENSE;

D O I：

10.1001/archneurol.2011.53

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD). Participants and Design: A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)-positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN- FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLD-TDP cases and all of the GRN- FTLD-TDP cases. Results: Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN- FTLD-TDP (median, 58.0 vs 61.0 years; P < .001), as was age at death (median, 65.5 vs 69.0 years; P < .001). Concomitant motor neuron disease was much less common in GRN+ FTLD-TDP vs GRN- FTLD-TDP (5.4% vs 26.3%; P < .001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations. Conclusion: GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.

引用

页码：488 / 497

页数：10

共 42 条

[31] Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C → T (Arg493X) mutation:: an international initiative [J].

Rademakers, Rosa ;

Baker, Matt ;

Gass, Jennifer ;

Adamson, Jennifer ;

Huey, Edward D. ;

Momeni, Parastoo ;

Spina, Salvatore ;

Coppola, Giovanni ;

Karydas, Anna M. ;

Stewart, Heather ;

Johnson, Nancy ;

Hsiung, Ging-Yuek ;

Kelley, Brendan ;

Kuntz, Karen ;

Steinbart, Ellen ;

Wood, Elisabeth McCarty ;

Yu, Chang-En ;

Josephs, Keith ;

Sorenson, Eric ;

Womack, Kyle B. ;

Weintraub, Sandra ;

Pickering-Brown, Stuart M. ;

Schopeld, Peter R. ;

Brooks, William S. ;

van Deerlin, Vivianna M. ;

Snowden, Julie ;

Clark, Christopher M. ;

Kertesz, Andrew ;

Boylan, Kevin ;

Ghetti, Bernardino ;

Neary, David ;

Schellenberg, Gerard D. ;

Beach, Thomas G. ;

Mesulam, Marsel ;

Mann, David ;

Grafman, Jordan ;

Mackenzie, Ian R. ;

Feldman, Howard ;

Bird, Thomas ;

Petersen, Ron ;

Knopman, David ;

Boeve, Bradley ;

Geschwind, Dan H. ;

Miller, Bruce ;

Wszolek, Zbigniew ;

Lippa, Carol ;

Bigio, Eileen H. ;

Dickson, Dennis ;

Graff-Radford, Neill ;

Hutton, Mike .

LANCET NEUROLOGY, 2007, 6 (10) :857-868

[32] The prevalence of frontotemporal dementia [J].

Ratnavalli, E ;

Brayne, C ;

Dawson, K ;

Hodges, JR .

NEUROLOGY, 2002, 58 (11) :1615-1621

[33] Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies [J].

Sampathu, Deepak M. ;

Neumann, Manuela ;

Kwong, Linda K. ;

Chou, Thomas T. ;

Micsenyi, Matthew ;

Truax, Adam ;

Bruce, Jennifer ;

Grossman, Murray ;

Trojanowski, John Q. ;

Lee, Virginia M. -Y. .

AMERICAN JOURNAL OF PATHOLOGY, 2006, 169 (04) :1343-1352

[34] A fast and flexible statistical model for large-scale population genotype data: Applications to inferring missing genotypes and haplotypic phase [J].

Scheet, P ;

Stephens, M .

AMERICAN JOURNAL OF HUMAN GENETICS, 2006, 78 (04) :629-644

[35] Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes [J].

Schymick, J. C. ;

Yang, Y. ;

Andersen, P. M. ;

Vonsattel, J. P. ;

Greenway, M. ;

Momeni, P. ;

Elder, J. ;

Chio, A. ;

Restagno, G. ;

Robberecht, W. ;

Dahlberg, C. ;

Mukherjee, O. ;

Goate, A. ;

Graff-Radford, N. ;

Caselli, R. J. ;

Hutton, M. ;

Gass, J. ;

Cannon, A. ;

Rademakers, R. ;

Singleton, A. B. ;

Hardiman, O. ;

Rothstein, J. ;

Hardy, J. ;

Traynor, B. J. .

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2007, 78 (07) :754-756

[36] Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion [J].

Shankaran, Sunita S. ;

Capell, Anja ;

Hruscha, Alexander T. ;

Fellerer, Katrin ;

Neumann, Manuela ;

Schmid, Bettina ;

Haass, Christian .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (03) :1744-1753

[37] EPITHELIN-1 AND EPITHELIN-2 - ISOLATION AND CHARACTERIZATION OF 2 CYSTEINE-RICH GROWTH-MODULATING PROTEINS [J].

SHOYAB, M ;

MCDONALD, VL ;

BYLES, C ;

TODARO, GJ ;

PLOWMAN, GD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (20) :7912-7916

[38] Corticobasal syndrome associated with the A9D Progranulin mutation [J].

Spina, Salvatore ;

Murrell, Jill R. ;

Huey, Edward D. ;

Wassermann, Eric M. ;

Pietrini, Pietro ;

Grafman, Jordan ;

Ghetti, Bernardino .

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 2007, 66 (10) :892-900

[39] Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations [J].

Van Deerlin, Vivianna M. ;

Wood, Elisabeth McCarty ;

Moore, Peachie ;

Yuan, Wuxing ;

Forman, Mark S. ;

Clark, Christopher M. ;

Neumann, Manuela ;

Kwong, Linda K. ;

Trojanowski, John Q. ;

Lee, Virginia M. -Y. ;

Grossman, Murray .

ARCHIVES OF NEUROLOGY, 2007, 64 (08) :1148-1153

[40] Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions [J].

Van Deerlin, Vivianna M. ;

Sleiman, Patrick M. A. ;

Martinez-Lage, Maria ;

Chen-Plotkin, Alice ;

Wang, Li-San ;

Graff-Radford, Neill R. ;

Dickson, Dennis W. ;

Rademakers, Rosa ;

Boeve, Bradley F. ;

Grossman, Murray ;

Arnold, Steven E. ;

Mann, David M. A. ;

Pickering-Brown, Stuart M. ;

Seelaar, Harro ;

Heutink, Peter ;

van Swieten, John C. ;

Murrell, Jill R. ;

Ghetti, Bernardino ;

Spina, Salvatore ;

Grafman, Jordan ;

Hodges, John ;

Spillantini, Maria Grazia ;

Gilman, Sid ;

Lieberman, Andrew P. ;

Kaye, Jeffrey A. ;

Woltjer, Randall L. ;

Bigio, Eileen H. ;

Mesulam, Marsel ;

al-Sarraj, Safa ;

Troakes, Claire ;

Rosenberg, Roger N. ;

White, Charles L., III ;

Ferrer, Isidro ;

Llado, Albert ;

Neumann, Manuela ;

Kretzschmar, Hans A. ;

Hulette, Christine Marie ;

Welsh-Bohmer, Kathleen A. ;

Miller, Bruce L. ;

Alzualde, Ainhoa ;

Lopez de Munain, Adolfo ;

McKee, Ann C. ;

Gearing, Marla ;

Levey, Allan I. ;

Lah, James J. ;

Hardy, John ;

Rohrer, Jonathan D. ;

Lashley, Tammaryn ;

Mackenzie, Ian R. A. ;

Feldman, Howard H. .

NATURE GENETICS, 2010, 42 (03) :234-U34

← 1 2 3 4 5 →