title: Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family.
abstract: BACKGROUND
  Progranulin gene (PGRN) haploinsufficiency was recently associated with ubiquitin-positive frontotemporal lobar degeneration linked to chromosome 17q21 (FTLDU-17).
  
  
  OBJECTIVE
  To assess whether PGRN genetic variability contributed to other common neurodegenerative brain diseases, such as Alzheimer disease (AD) or Parkinson disease (PD).
  
  
  METHODS
  Mutation analysis of PGRN.
  
  
  METHODS
  Memory Clinic of the Middelheim General Hospital. Patients We analyzed 666 Belgian patients with AD and 255 with PD.
  
  
  METHODS
  Results of PGRN sequencing, PGRN transcript analysis, short tandem repeat genotyping, and neuropathologic analysis.
  
  
  RESULTS
  We identified 2 patients with AD and 1 patient with PD who carried the null mutation IVS0 + 5G>C, which we reported earlier in an extensively characterized Belgian founder family, DR8, segregating FTLDU. Postmortem pathologic diagnosis of the patient with PD revealed both FTLDU and Lewy body pathologic features. In addition, we identified in PGRN only 1 other null mutation, the nonsense mutation p.Arg535X, in 1 patient with probable AD. However, in vitro analysis predicted a PGRN C-truncated protein, although it remains to be elucidated if this shortened transcript leads to haploinsufficiency.
  
  
  CONCLUSIONS
  Our mutation data indicated that null mutations are rare in patients with AD (3/666 = 0.45%) and PD (1/255 = 0.39%). Also, AD and PD clinical diagnoses in patients who carry PGRN null mutations likely result from etiologic heterogeneity rather than PGRN haploinsufficiency.
authors.affiliation: VIB Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.forename: Karen
authors.initials: K
authors.lastname: Nuytemans
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Ilse
authors.initials: I
authors.lastname: Gijselinck
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
authors.forename: Samir
authors.initials: S
authors.lastname: Kumar-Singh
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Pickut
authors.forename: Philippe
authors.initials: P
authors.lastname: Pals
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
authors.forename: Veerle
authors.initials: V
authors.lastname: Bogaerts
authors.forename: Tim
authors.initials: T
authors.lastname: De Pooter
authors.forename: Sally
authors.initials: S
authors.lastname: Serneels
authors.forename: Marleen
authors.initials: M
authors.lastname: Van den Broeck
authors.forename: Ivy
authors.initials: I
authors.lastname: Cuijt
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.forename: Patrick
authors.initials: P
authors.lastname: Santens
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
mesh_terms: D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D001344:Autopsy; D001530:Belgium / Q000453:epidemiology; D001921:Brain / Q000473:pathology; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D020961:Lewy Body Disease / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D000077153:Progranulins; D020080:Tandem Repeat Sequences / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin