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

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

来源：Archives of Neurology, 2007, 64(10): 1436-1446.

DOI：10.1001/archneur.64.10.1436

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 haploin-sufficiency.

• 出版日期2007-10