title: Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration.
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).
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA. chenplot@mail.med.upenn.edu
authors.forename: Alice S
authors.initials: AS
authors.lastname: Chen-Plotkin
authors.forename: Maria
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authors.lastname: Martinez-Lage
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authors.lastname: Sleiman
authors.forename: William
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authors.lastname: Hu
authors.forename: Robert
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authors.forename: Neill R
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authors.lastname: Seelaar
authors.forename: Jill R
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authors.forename: Bernardino
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authors.forename: Salvatore
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authors.forename: Randall L
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authors.lastname: Woltjer
authors.forename: Marsel
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authors.lastname: Mesulam
authors.forename: Eileen
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authors.lastname: Bigio
authors.forename: Albert
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authors.lastname: Lladó
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Ainhoa
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authors.lastname: Alzualde
authors.forename: Fermin
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authors.lastname: Moreno
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Howard H
authors.initials: HH
authors.lastname: Feldman
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Marc
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authors.lastname: Cruts
authors.forename: Sebastiaan
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authors.lastname: Engelborghs
authors.forename: Peter P
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authors.lastname: De Deyn
authors.forename: Christine
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authors.lastname: Van Broeckhoven
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Allison
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authors.lastname: Goate
authors.forename: Matthew P
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authors.lastname: Frosch
authors.forename: Peter F
authors.initials: PF
authors.lastname: Riederer
authors.forename: Nenad
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authors.lastname: Bogdanovic
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
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authors.lastname: Trojanowski
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authors.lastname: Van Deerlin
mesh_terms: D000368:Aged; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000175:diagnosis* / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics; D000077153:Progranulins; D011498:Protein Precursors / Q000235:genetics*
chemical_list: C492314:GRN protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011498:Protein Precursors