Progranulin mutations in ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
Abstract
Two genetically distinct types of frontotemporal dementia (FTD) are linked to chromosome 17q21. FTD with parkinsonism (FTDP-17) results from mutations in the gene encoding microtubule associated protein tau (MAPT) and is associated with tau deposition in the patient's brain. An increasing number of FTD families are linked to 17q21 in the absence of a demonstrable MAPT mutation. Brains of these patients do not show tau deposits, but tau-negative intra- and perinuclear inclusions of unknown composition that are immunoreactive to ubiquitin (FTDU-17). These ubiquitin inclusions are located in the cytoplasm or nucleus of predominantly neuronal cells of affected brain regions. By extensive segregation analyses in conclusively linked FTDU-17 families, the candidate region was reduced to a 6.2 Mb segment containing MAPT; however, genomic sequencing of MAPT in FTDU-17 patients excluded disease-causing mutations. Further, the linked region was characterized by the presence of multiple low-copy repeat regions associated with genomic instability. However, we excluded genomic rearrangements as the cause of FTDU-17. Subsequent sequencing of positional candidate genes identified loss-of-function mutations in the gene encoding progranulin (PGRN), a growth factor involved in multiple physiological processes such as cellular proliferation and survival and tissue repair, and pathological processes including tumorigenesis. In a Belgian FTD patient series, the prevalence of PGRN mutations was 3.5…
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From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [38]
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- Authors
- Cruts, M., Kumar-Singh, S., & Van Broeckhoven, C.
- Affiliations
- VIB-UAntwerp Center for Molecular Neurology (BE)
- ORCID
- Cruts, Marc
- Venue
- Current Alzheimer Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2006-12-01
- Volume
- 3
- Issue
- 5
- Pages
- 485-491
- ISSN
- 1567-2050 (ISSN-L)
- OpenAlex
- W2166107584
- Cited by
- 67
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 6 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 2 · 2012: 2
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Alzheimer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- progranulin, frontotemporal dementia, chromosome 17q21, ubiquitin-positive inclusions, MAPT, haploinsufficiency, neuronal survival, neurodegeneration, genomic instability, Alzheimer's disease, neurodegenerative disease progression
- MeSH terms
- Progranulins, Chromosome Mapping, Chromosomes, Human, Pair 17, Dementia, Humans, Genetic Linkage, Mutation, Ubiquitin, Intercellular Signaling Peptides and Proteins
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