Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family.
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.
Brouwers
Nathalie
N
VIB Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, University of Antwerp CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium.
Nuytemans
Karen
K
van der Zee
Julie
J
Gijselinck
Ilse
I
Engelborghs
Sebastiaan
S
Theuns
Jessie
J
Kumar-Singh
Samir
S
Pickut
Barbara A
BA
Pals
Philippe
P
Dermaut
Bart
B
Bogaerts
Veerle
V
De Pooter
Tim
T
Serneels
Sally
S
Van den Broeck
Marleen
M
Cuijt
Ivy
I
Mattheijssens
Maria
M
Peeters
Karin
K
Sciot
Raf
R
Martin
Jean-Jacques
JJ
Cras
Patrick
P
Santens
Patrick
P
Vandenberghe
Rik
R
De Deyn
Peter P
PP
Cruts
Marc
M
Van Broeckhoven
Christine
C
Sleegers
Kristel
K
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
D018389:Codon, Nonsense; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D025801:Ubiquitin