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Nathalie Brouwers, MSc; Karen Nuytemans, MSc; Julie van der Zee, MSc; Ilse Gijselinck, MSc; Sebastiaan Engelborghs, MD, PhD; Jessie Theuns, PhD; Samir Kumar-Singh, MD, PhD; Barbara A. Pickut, MD; Philippe Pals, MD, PhD; Bart Dermaut, MD, PhD; Veerle Bogaerts, MPharm; Tim De Pooter, BS; Sally Serneels, BS; Marleen Van den Broeck, BS; Ivy Cuijt, BS; Maria Mattheijssens, BSN; Karin Peeters, BSN; Raf Sciot, MD, PhD; Jean-Jacques Martin, MD, PhD; Patrick Cras, MD, PhD; Patrick Santens, MD; Rik Vandenberghe, MD; Peter P. De Deyn, MD, PhD; Marc Cruts, PhD; Christine Van Broeckhoven, PhD, DSc; Kristel Sleegers, MD, PhD

Arch Neurol. 2007;64(10):1436-1446.

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  We analyzed 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.

Author Affiliations: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB (Mss Brouwers, Nuytemans, van der Zee, Gijselinck, Bogaerts, Serneels, Van den Broeck, Cuijt, Mattheijssens, and Peeters, Drs Theuns, Kumar-Singh, Cruts, Van Broeckhoven, and Sleegers, and Mr De Pooter); Laboratory of Neurogenetics (Mss Brouwers, Nuytemans, van der Zee, Gijselinck, Bogaerts, Serneels, Van den Broeck, Cuijt, Mattheijssens, and Peeters, Drs Theuns, Kumar-Singh, Cruts, Van Broeckhoven, and Sleegers, and Mr De Pooter), Laboratory of Neurochemistry and Behaviour (Drs Engelborghs and De Deyn), and Laboratory of Neuropathology (Dr Martin), Institute Born-Bunge; University of Antwerp (Mss Brouwers, Nuytemans, van der Zee, Gijselinck, Engelborghs, Bogaerts, Serneels, Van den Broeck, Cuijt, Mattheijssens, and Peeters, Drs Engelborghs, Theuns, Kumar-Singh, Martin, De Deyn, Cruts, Van Broeckhoven, and Sleegers, and Mr De Pooter); Memory Clinic and Division of Neurology, ZNA Middelheim General Hospital (Drs Engelborghs, Pickut, and De Deyn); and Division of Neurology, University Hospital Antwerp (Drs Pals and Cras), Antwerpen; Division of Neurology, Ghent University Hospital, Ghent (Drs Dermaut and Santens); and Divisions of Pathology (Dr Sciot) and Neurology (Dr Vandenberghe), University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium.

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