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Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration

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Chen-Plotkin, Alice S., Martinez-Lage, Maria, Sleiman, Patrick M. A., Hu, William, Greene, Robert, Wood, Elisabeth McCarty, Bing, Shaoxu, Grossman, Murray +47 more·2011·Archives of Neurology
DOI 10.1001/archneurol.2011.53PMC PMC3160280
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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.

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  • Correlation studies between molecular genetics and neuropathology indicate that for several autosomal dominant dementias, the presenting clinical phenotype may vary widely, from various dementia subtypes to parkinsonism to motor neuron disease-like, even among individuals with the same causative mutation.

    “Correlation studies between molecular genetics and neuropathology also indicate that for several autosomal dominant dementias, the presenting clinical phenotype may vary widely, from various dementia subtypes to parkinsonism to motor neuron disease-like, even among individuals with the same causative mutation (44-47).”

    From Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010 (2012) · cites this paper as [44]

    The introductory passage following the Abstract conclusion (page unavailable) says GRN-associated frontotemporal lobar degeneration is clinically heterogeneous even among family members with the same mutation. The Results report dementia and parkinsonian diagnoses, but describe motor neuron disease as uncommon and concomitant, not a typical presenting phenotype. This paper addresses GRN-associated disease, so it does not by itself establish the claim across several autosomal dominant dementias. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Phenotype is not rigidly linked to etiology and may be moldable to a large extent by an individual's genetic and epigenetic background and/or total environmental exposure.

    “These findings suggest that phenotype is not rigidly linked to etiology and may be moldable to a large extent by an individual's genetic and epigenetic background and/or total environmental exposure.”

    From Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010 (2012) · cites this paper as [44]

    The introductory passage following the Abstract conclusion says GRN-associated frontotemporal lobar degeneration is clinically heterogeneous even among relatives with the same mutation, and identifies nonmendelian genetic risk factors. This supports the suggestion that phenotype is not rigidly determined by the causal mutation, but the paper does not establish a large effect of epigenetic background or environmental exposure. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 38

  1. [1]Ratnavalli E Brayne C Dawson K Hodges JR The prevalence of frontotemporal dementia. Neurology 2002 58 11 1615 1621 12058088
  2. [2]McKhann GM Albert MS Grossman M Miller B Dickson D Trojanowski JQ Work Group on Frontotemporal Dementia and Pick's Disease Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol 2001 58 11 1803 1809 11708987
  3. [3]Neary D Snowden JS Gustafson L Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998 51 6 1546 1554 9855500
  4. [4]Mesulam MM Primary progressive aphasia—a language-based dementia. NEngl J Med 2003 349 16 1535 1542 14561797
  5. [6]Poorkaj P Bird TD Wijsman E Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998 43 6 815 825 9629852
  6. [8]Cruts M Gijselinck I van der Zee J Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006 442 7105 920 924 16862115
  7. [9]Benajiba L Le Ber I Camuzat A French Clinical and Genetic Research Network on Frontotemporal Lobar Degeneration/Frontotemporal Lobar Degeneration with Motoneuron Disease. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol 2009 65 4 470 473 19350673
  8. [10]Bateman A Belcourt D Bennett H Lazure C Solomon S Granulins, a novel class of peptide from leukocytes. Biochem Biophys Res Commun 1990 173 3 1161 1168 2268320
  9. [11]Shoyab M McDonald VL Byles C Todaro GJ Plowman GD Epithelins 1 and 2: isolation and characterization of two cysteine-rich growth-modulating proteins. Proc Natl Acad Sci U S A 1990 87 20 7912 7916 2236009 PMC54861
  10. [12]Bhandari V Palfree RG Bateman A Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. Proc Natl Acad Sci U S A 1992 89 5 1715 1719 1542665 PMC48523
  11. [14]Plowman GD Green JM Neubauer MG The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth. J Biol Chem 1992 267 18 13073 13078 1618805
  12. [15]Zhu J Nathan C Jin W Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 2002 111 6 867 878 12526812
  13. [16]Gass J Cannon A Mackenzie IR Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006 15 20 2988 3001 16950801
  14. [17]Le Ber I van der Zee J Hannequin D French Research Network on FTD/FTD-MND. Progranulin null mutations in both sporadic and familial frontotemporal dementia. Hum Mutat 2007 28 9 846 855 17436289
  15. [18]Cruts M Van Broeckhoven C Loss of progranulin function in frontotemporal lobar degeneration. Trends Genet 2008 24 4 186 194 18328591
  16. [19]Chen-Plotkin AS Xiao J Geser F Brain progranulin expression in GRN-associated frontotemporal lobar degeneration. Acta Neuropathol 2010 119 1 111 122 19649643 PMC3104467
  17. [20]Mukherjee O Wang J Gitcho M Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia. Hum Mutat 2008 29 4 512 521 18183624 PMC2756561
  18. [21]Shankaran SS Capell A Hruscha AT Missense mutations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions reduce progranulin production and secretion. J Biol Chem 2008 283 3 1744 1753 17984093
  19. [22]Gijselinck I van der Zee J Engelborghs S Progranulin locus deletion in frontotemporal dementia. Hum Mutat 2008 29 1 53 58 18157829
  20. [23]Leverenz JB Yu CE Montine TJ A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain 2007 130 pt 5 1360 1374 17439980
  21. [24]Rademakers R Baker M Gass J Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative. Lancet Neurol 2007 6 10 857 868 17826340
  22. [25]Benussi L Binetti G Sina E A novel deletion in progranulin gene is associated with FTDP-17 and CBS. Neurobiol Aging 2008 29 3 427 435 17157414
  23. [26]Brouwers N Nuytemans K van der Zee J Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. Arch Neurol 2007 64 10 1436 1446 17923627
  24. [27]Mackenzie IR Baker M Pickering-Brown S The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 2006 129 pt 11 3081 3090 17071926
  25. [28]Josephs KA Ahmed Z Katsuse O Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol 2007 66 2 142 151 17278999
  26. [29]Schymick JC Yang Y Andersen PM Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis–frontotemporal dementia phenotypes. J Neurol Neurosurg Psychiatry 2007 78 7 754 756 17371905 PMC2117704
  27. [30]van Swieten JC Heutink P Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. Lancet Neurol 2008 7 10 965 974 18771956
  28. [31]Van Deerlin VM Sleiman PM Martinez-Lage M Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 2010 42 3 234 239 20154673 PMC2828525
  29. [32]Van Deerlin VM Wood EM Moore P Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations. Arch Neurol 2007 64 8 1148 1153 17698705
  30. [33]Sampathu DM Neumann M Kwong LK Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 2006 169 4 1343 1352 17003490 PMC1780184
  31. [34]Neumann M Sampathu DM Kwong LK Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006 314 5796 130 133 17023659
  32. [35]Scheet P Stephens M A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 2006 78 4 629 644 16532393 PMC1424677
  33. [36]Brouwers N Sleegers K Engelborghs S Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 2008 71 9 656 664 18565828
  34. [37]Mackenzie IR The neuropathology and clinical phenotype of FTD with progranulin mutations. Acta Neuropathol 2007 114 1 49 54 17458552
  35. [38]Van Deerlin VM Wood EM Moore P Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations. Arch Neurol 2007 64 8 1148 1153 17698705
  36. [40]Pickering-Brown SM Baker M Gass J Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain 2006 129 pt 11 3124 3126 17071927
  37. [41]Kelley BJ Haidar W Boeve BF Prominent phenotypic variability associated with mutations in progranulin. Neurobiol Aging 2009 5 739 751 17949857 PMC3164546
  38. [42]Spina S Murrell JR Huey ED Corticobasal syndrome associated with the A9D progranulin mutation. J Neuropathol Exp Neurol 2007 66 10 892 900 17917583

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Authors
Chen-Plotkin, A. S., Martinez-Lage, M., Sleiman, P. M. A., Hu, W., Greene, R., Wood, E. M., Bing, S., Grossman, M., Schellenberg, G. D., Hatanpaa, K. J., Weiner, M. F., White, C. L., Brooks, W. S., Halliday, G. M., Kril, J. J., Gearing, M., Beach, T. G., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Pickering-Brown, S. M., Snowden, J., van Swieten, J. C., Heutink, P., Seelaar, H., Murrell, J. R., Ghetti, B., Spina, S., Grafman, J., Kaye, J. A., Woltjer, R. L., Mesulam, M., Bigio, E., Lladó, A., Miller, B. L., Alzualde, A., Moreno, F., Rohrer, J. D., Mackenzie, I. R. A., Feldman, H. H., Hamilton, R. L., Cruts, M., Engelborghs, S., De Deyn, P. P., Van Broeckhoven, C., Bird, T. D., Cairns, N. J., Goate, A., Frosch, M. P., Riederer, P. F., Bogdanovic, N., Lee, V. M. Y., Trojanowski, J. Q., & Van Deerlin, V. M.
Affiliations
  • Universitat Autònoma de Barcelona (ES)
  • University of Siena (IT)
  • Northwestern University (US)
ORCID
Venue
Archives of Neurology
Publisher
American Medical Association (AMA)
Published
2011-04-11
Volume
68
Issue
4
Pages
488
ISSN
0003-9942 (ISSN-L)
DOI
10.1001/archneurol.2011.53
PMC
PMC3160280
OpenAlex
W2130071233
Cited by
120
References
5
Citations by year
2026: 5 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 4 · 2019: 5 · 2018: 10 · 2017: 9 · 2016: 11 · 2015: 11 · 2014: 10 · 2013: 11 · 2012: 15
FWCI
8.12
Type
journal article
Language
en
Open access
Locations
  • Archives of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • Arizona Department of Health Services
  • Wellcome Trust (089701, 75480)
  • Deutsche Forschungsgemeinschaft
  • Bundesministerium für Bildung und Forschung
  • Belgian Federal Science Policy Office
  • Eusko Jaurlaritza
  • Fonds Wetenschappelijk Onderzoek
  • Universiteit Antwerpen
  • Vlaamse regering
  • Arizona Biomedical Research Commission
  • National Institutes of Health (5p50ns038372-10)
  • Canadian Institutes of Health Research (75480)
  • Medical Research Council
  • National Health and Medical Research Council
  • Bijzonder Onderzoeksfonds UGent
  • National Institute on Aging (AG08702, AG010133, AG15116, P30AG010129, P30AG010133, AG 05-133, AG033101, AG13854, AG 10161, AG 08671, AG 13846, AG03991, AG-02219, P30AG012300, AG 025688, R37AG018440, AG03949, AG-005136, R01AG018440, AG 05142, AG008017, P50AG005133, AG 16573, P30AG028377, AG 16574, AG 05138, P50AG005131, AG-19610, P50AG005138, P50AG016570, P01AG003949, P30AG010124, P50AG016573, AG 16570, R01AG015116, AG 16582, P01AG017586, AG010129, AG 18440, AG17586, P30AG008017, AG-10124, P30AG010161, AG005131, AG028377, AG-10129, P50AG016582, P50AG008702, K08AG033101, P50AG005681, P50AG005142, P50AG008671, P30AG019610, P50AG005146, P01AG003991, AG019724, P30AG013846, P50AG005136, P50AG005134, P30AG013854, AG 05146, P50AG025688, AG 12300, AG 05134, P01AG002219, AG005681, P01AG019724, P30AG062421, P50AG016574)
  • National Institute of Neurological Disorders and Stroke (NS53488, P01NS044233, NS065782, P50-NS-038372, NS-44266, NS-044233, NS-15655, NS 038372, P01NS015655, P50NS053488, R01NS065782, R01NS044266)
  • National Center for Research Resources (UL1RR025741)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
progranulin, progranulin mutations, frontotemporal lobar degeneration, FTLD-TDP, TDP-43, age of onset, motor neuron disease, novel mutations, haplotypes, parkinsonian features, genotype-phenotype correlation, chromosome 17
MeSH terms
Progranulins, Aged, Female, Genetic Markers, Humans, Male, Middle Aged, Mutation, Protein Precursors, Parkinsonian Disorders, Intercellular Signaling Peptides and Proteins, Frontotemporal Lobar Degeneration

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