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). 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 language | English (US) |
|---|---|
| Pages (from-to) | 1436-1446 |
| Number of pages | 11 |
| Journal | Archives of Neurology |
| Volume | 64 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Arts and Humanities (miscellaneous)
- Clinical Neurology
Cite this
Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. / 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.
In: Archives of Neurology, Vol. 64, No. 10, 01.10.2007, p. 1436-1446.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family
AU - Brouwers, Nathalie
AU - Nuytemans, Karen
AU - Van Der Zee, Julie
AU - Gijselinck, Ilse
AU - Engelborghs, Sebastiaan
AU - Theuns, Jessie
AU - Kumar-Singh, Samir
AU - Pickut, Barbara A.
AU - Pals, Philippe
AU - Dermaut, Bart
AU - Bogaerts, Veerle
AU - De Pooter, Tim
AU - Serneels, Sally
AU - Van Den Broeck, Marleen
AU - Cuijt, Ivy
AU - Mattheijssens, Maria
AU - Peeters, Karin
AU - Sciot, Raf
AU - Martin, Jean Jacques
AU - Cras, Patrick
AU - Santens, Patrick
AU - Vandenberghe, Rik
AU - De Deyn, Peter P.
AU - Cruts, Marc
AU - Van Broeckhoven, Christine
AU - Sleegers, Kristel
PY - 2007/10/1
Y1 - 2007/10/1
N2 - 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.
AB - 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.
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U2 - 10.1001/archneur.64.10.1436
DO - 10.1001/archneur.64.10.1436
M3 - Article
VL - 64
SP - 1436
EP - 1446
JO - Archives of Neurology
JF - Archives of Neurology
SN - 0003-9942
IS - 10
ER -