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Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
Abstract
Frontotemporal dementia (FTD) with ubiquitin-immunoreactive neuronal inclusions (both cytoplasmic and nuclear) of unknown nature has been linked to a chromosome 17q21 region (FTDU-17) containing MAPT (microtubule-associated protein tau). FTDU-17 patients have consistently been shown to lack a tau-immunoreactive pathology, a feature characteristic of FTD with parkinsonism linked to mutations in MAPT (FTDP-17). Furthermore, in FTDU-17 patients, mutations in MAPT and genomic rearrangements in the MAPT region have been excluded by both genomic sequencing and fluorescence in situ hybridization on mechanically stretched chromosomes. Here we demonstrate that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis. Besides the production of truncated PGRN proteins due to premature stop codons, we identified a mutation within the splice donor site of intron 0 (IVS0 + 5G > C), indicating loss of the mutant transcript by nuclear degradation. The finding was made within an extensively documented Belgian FTDU-17 founder family. Transcript and protein analyses confirmed the absence of the mutant allele and a reduction in the expression of PGRN. We also identified a mutation (c.3G > A) in the Met1 translation initiation codon, indicating loss of PGRN due to lack of translation of the mutant allele. Our data provide evidence that PGRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, PGRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of PGRN in FTD pathogenesis.
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“Upon signaling from neurons, PLP is exocytosed to the plasma membrane to form the myelin sheath.37”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [37]
In the citing paper
“A proteomic relationship between AD and FTD is supported by the fact that mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) protein cause microglial dysfunction and lead to AD39,40, whereas mutations in the progranulin (PGRN) protein also cause microglial dysfunction and lead to FTD41–43.”
In the citing paper
“We performed power calculations to forecast the number of additional PD cases needed to achieve genome-wide significance at 80% power for a variant with a minor allele frequency of 21.3% and an effect estimate of 0.047 (32). Assuming that future data is well-harmonized with current data and that disease prevalence is 0.5%, we estimated that we would need a total of ~99K cases, ~2.3 times more than”
From Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies (2019) · cites this paper as [32]
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Metadata
- Authors
- Cruts, M., Gijselinck, I., van der Zee, J., Engelborghs, S., Wils, H., Pirici, D., Rademakers, R., Vandenberghe, R., Dermaut, B., Martin, J.-J., van Duijn, C., Peeters, K., Sciot, R., Santens, P., De Pooter, T., Mattheijssens, M., Van den Broeck, M., Cuijt, I., Vennekens, K., De Deyn, P. P., Kumar-Singh, S., & Van Broeckhoven, C.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- University of Antwerp (BE)
- Ghent University Hospital (BE)
- KU Leuven (BE)
- ORCID
- Venue
- Nature
- Published
- 2006-07-16
- Volume
- 442
- Issue
- 7105
- Pages
- 920-924
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2005731595
- Cited by
- 1,512
- References
- 25
- Citations by year
- 2026: 32 · 2025: 50 · 2024: 53 · 2023: 56 · 2022: 52 · 2021: 73 · 2020: 67 · 2019: 83 · 2018: 68 · 2017: 82 · 2016: 78 · 2015: 55 · 2014: 78 · 2013: 77 · 2012: 90
- FWCI
- 77.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- progranulin, frontotemporal dementia, chromosome 17q21, haploinsufficiency, splice donor site mutation, premature stop codon, MAPT, tau protein, neurodegeneration
- MeSH terms
- Progranulins, Belgium, Chromosomes, Human, Pair 17, Dementia, DNA Mutational Analysis, Frontal Lobe, Humans, Genetic Linkage, Mutation, Temporal Lobe, Physical Chromosome Mapping, RNA Splice Sites, Ubiquitin, Intercellular Signaling Peptides and Proteins
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