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- PMID: 21482928
- UKPMCID: 21482928
- DOI: 10.1001/archneurol.2011.53
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Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.
Chen-Plotkin, Alice S; Martinez-Lage, Maria; Sleiman, Patrick M A; Hu, William; Greene, Robert; Wood, Elisabeth McCarty; Bing, Shaoxu; Grossman, Murray; Schellenberg, Gerard D; Hatanpaa, Kimmo J; Weiner, Myron F; White, Charles L; Brooks, William S; Halliday, Glenda M; Kril, Jillian J; Gearing, Marla; Beach, Thomas G; Graff-Radford, Neill R; Dickson, Dennis W; Rademakers, Rosa; Boeve, Bradley F; Pickering-Brown, Stuart M; Snowden, Julie; van Swieten, John C; Heutink, Peter; Seelaar, Harro; Murrell, Jill R; Ghetti, Bernardino; Spina, Salvatore; Grafman, Jordan; Kaye, Jeffrey A; Woltjer, Randall L; Mesulam, Marsel; Bigio, Eileen; Lladó, Albert; Miller, Bruce L; Alzualde, Ainhoa; Moreno, Fermin; Rohrer, Jonathan D; Mackenzie, Ian R A; Feldman, Howard H; Hamilton, Ronald L; Cruts, Marc; Engelborghs, Sebastiaan; De Deyn, Peter P; Van Broeckhoven, Christine; Bird, Thomas D; Cairns, Nigel J; Goate, Allison; Frosch, Matthew P; Riederer, Peter F; Bogdanovic, Nenad; Lee, Virginia M Y; Trojanowski, John Q; Van Deerlin, Vivianna M
Archives of neurology. 2011;68(4):488-97.
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Full-text held externally
- PMID: 21482928
- UKPMCID: 21482928
- DOI: 10.1001/archneurol.2011.53
Abstract
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.
Bibliographic metadata
- Chen-Plotkin, Alice S
- Martinez-Lage, Maria
- Sleiman, Patrick M A
- Hu, William
- Greene, Robert
- Wood, Elisabeth McCarty
- Bing, Shaoxu
- Grossman, Murray
- Schellenberg, Gerard D
- Hatanpaa, Kimmo J
- Weiner, Myron F
- White, Charles L
- Brooks, William S
- Halliday, Glenda M
- Kril, Jillian J
- Gearing, Marla
- Beach, Thomas G
- Graff-Radford, Neill R
- Dickson, Dennis W
- Rademakers, Rosa
- Boeve, Bradley F
- Pickering-Brown, Stuart M
- Snowden, Julie
- van Swieten, John C
- Heutink, Peter
- Seelaar, Harro
- Murrell, Jill R
- Ghetti, Bernardino
- Spina, Salvatore
- Grafman, Jordan
- Kaye, Jeffrey A
- Woltjer, Randall L
- Mesulam, Marsel
- Bigio, Eileen
- Lladó, Albert
- Miller, Bruce L
- Alzualde, Ainhoa
- Moreno, Fermin
- Rohrer, Jonathan D
- Mackenzie, Ian R A
- Feldman, Howard H
- Hamilton, Ronald L
- Cruts, Marc
- Engelborghs, Sebastiaan
- De Deyn, Peter P
- Van Broeckhoven, Christine
- Bird, Thomas D
- Cairns, Nigel J
- Goate, Allison
- Frosch, Matthew P
- Riederer, Peter F
- Bogdanovic, Nenad
- Lee, Virginia M Y
- Trojanowski, John Q
- Van Deerlin, Vivianna M
- 75480, Canadian Institutes of Health Research, Canada
- AG005131, NIA NIH HHS, United States
- AG005136, NIA NIH HHS, United States
- AG005681, NIA NIH HHS, United States
- AG008017, NIA NIH HHS, United States
- AG010129, NIA NIH HHS, United States
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- AG15116, NIA NIH HHS, United States
- AG16570, NIA NIH HHS, United States
- AG16573, NIA NIH HHS, United States
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- AG17586, NIA NIH HHS, United States
- AG18440, NIA NIH HHS, United States
- AG19610, NIA NIH HHS, United States
- NS038372, NINDS NIH HHS, United States
- NS044233, NINDS NIH HHS, United States
- NS065782, NINDS NIH HHS, United States
- NS15655, NINDS NIH HHS, United States
- NS44266, NINDS NIH HHS, United States
- NS53488, NINDS NIH HHS, United States
- P01 AG017586-09, NIA NIH HHS, United States
- P30 AG008017-21, NIA NIH HHS, United States
- P30 AG010161-14, NIA NIH HHS, United States
- P50 AG005134-27, NIA NIH HHS, United States
- P50 AG016582-10, NIA NIH HHS, United States
- R01 NS065782-03, NINDS NIH HHS, United States
- , Medical Research Council, United Kingdom
- , Wellcome Trust, United Kingdom