Alzheimer and Parkinson Diagnoses in Progranulin Null Mutation Carriers in an Extended Founder Family
- 1 October 2007
- journal article
- case report
- Published by American Medical Association (AMA) in Archives of Neurology
- Vol. 64 (10), 1436-1446
- https://doi.org/10.1001/archneur.64.10.1436
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 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.Keywords
This publication has 17 references indexed in Scilit:
- Progranulin and frontotemporal lobar degenerationActa Neuropathologica, 2007
- Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementiaHuman Mutation, 2007
- HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin‐positive, tau‐negative inclusions caused by a missense mutation in the signal peptide of progranulinAnnals of Neurology, 2006
- Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degenerationHuman Molecular Genetics, 2006
- Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17Nature, 2006
- Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21Nature, 2006
- Tau is central in the genetic Alzheimer–frontotemporal dementia spectrumTrends in Genetics, 2005
- Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesisJournal of Molecular Medicine, 2003
- Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effectsJournal of Neurology, Neurosurgery & Psychiatry, 2003
- Progression of Parkinsonism and Loss of Cognitive Function in Alzheimer DiseaseArchives of Neurology, 2000