Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family

Nathalie Brouwers, Karen Nuytemans, Julie Van Der Zee, Ilse Gijselinck, Sebastiaan Engelborghs, Jessie Theuns, Samir Kumar-Singh, Barbara A. Pickut, Philippe Pals, Bart Dermaut, Veerle Bogaerts, Tim De Pooter, Sally Serneels, Marleen Van Den Broeck, Ivy Cuijt, Maria Mattheijssens, Karin Peeters, Raf Sciot, Jean Jacques Martin, Patrick CrasPatrick Santens, Rik Vandenberghe, Peter P. De Deyn, Marc Cruts, Christine Van Broeckhoven, Kristel Sleegers

Research output: Contribution to journalArticlepeer-review

122 Scopus citations


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). Design: Mutation analysis of PGRN. Setting: Memory Clinic of the Middelheim General Hospital. Patients:Weanalyzed 666 Belgian patients with AD and 255 with PD. Main Outcome Measures: 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.

Original languageEnglish (US)
Pages (from-to)1436-1446
Number of pages11
JournalArchives of neurology
Issue number10
StatePublished - Oct 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology


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