Progranulin genetic variability contributes to amyotrophic lateral sclerosis
Abstract
OBJECTIVES: Null mutations in progranulin (PGRN) cause ubiquitin-positive frontotemporal dementia (FTD) linked to chromosome 17q21 (FTDU-17). Here we examined PGRN genetic variability in amyotrophic lateral sclerosis (ALS), a neurodegenerative motor neuron disease that overlaps with FTD at a clinical, pathologic, and epidemiologic level. METHODS: We sequenced all exons, exon-intron boundaries, and 5' and 3' regulatory regions of PGRN in a Belgian sample of 230 patients with ALS. The frequency of observed genetic variants was determined in 436 healthy control individuals. The contribution of eight frequent polymorphisms to ALS risk, onset age, and survival was assessed in an association study in the Belgian sample and a replication series of 308 Dutch patients with ALS and 345 Dutch controls. RESULTS: In patients with ALS we identified 11 mutations, 5 of which were predicted to affect PGRN protein sequence or levels (four missense mutations and one 5' regulatory variant). Moreover, common variants (rs9897526, rs34424835, and rs850713) and haplotypes were significantly associated with a reduction in age at onset and a shorter survival after onset of ALS in both the Belgian and the Dutch studies. CONCLUSION: PGRN acts as a modifier of the course of disease in patients with amyotrophic lateral sclerosis, through earlier onset and shorter survival.
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Five progranulin mutations (four missense and one 5′ regulatory variant) are linked to earlier ALS onset and shorter survival after onset.
“Five progranulin mutations (four missense and one 5′ regulatory variant) are associated with reduction in age at onset and shorter survival after onset of ALS”
From Microglia in neurodegeneration (2018) · cites this paper as [146]
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- Authors
- Sleegers, K., Brouwers, N., Maurer-Stroh, S., van Es, M. A., Damme, P. V., van Vught, P. W. J., van der Zee, J., Serneels, S., Pooter, T. D., Van den Broeck, M., Cruts, M., Schymkowitz, J., Jonghe, P. D., Rousseau, F., van den Berg, L. H., Robberecht, W., & Broeckhoven, C. V.
- Affiliations
- University of Antwerp (BE)
- From the Neurodegenerative Brain Diseases Group (K.S., N.B., J.v.d.Z., S.S., T.D.P., M.V.d.B., M.C., C.V.B.) and Neurogenetics Group (P.D.J.), Department of Molecular Genetics, and SWITCH Laboratory (S.M.-S., J.S., F.R.) VIB, University of Antwerp (K.S., N.B., J.v.d.Z., S.S., T.D.P., M.V.d.B., M.C., P.D.J., C.V.B.), Antwerpen; University Brussels (VUB) (S.M.-S., J.S., F.R.); Department of Neurology (M.A.v.E., P.W.J.v.V., L.H.v.d.B.), Rudolf Magnus Institute of Neuroscience, University Medical Center...
- ORCID
- Venue
- Neurology
- Published
- 2008-07-22
- Volume
- 71
- Issue
- 4
- Pages
- 253-259
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W1995715453
- Cited by
- 161
- References
- 40
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 7 · 2017: 3 · 2016: 7 · 2015: 13 · 2014: 7 · 2013: 11 · 2012: 19
- FWCI
- 12.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- progranulin, amyotrophic lateral sclerosis, missense mutations, haplotypes, age of onset, clinical course, frontotemporal dementia, 17q21, genetic association
- MeSH terms
- Progranulins, Adult, Aged, Amyotrophic Lateral Sclerosis, Belgium, Dementia, DNA Mutational Analysis, Female, Genetic Markers, Genetic Testing, Genotype, Haplotypes, Humans, Male, Middle Aged, Mutation, Netherlands, Polymorphism, Genetic, Genetic Variation, Survival Rate, Age of Onset, Genetic Predisposition to Disease, Mutation, Missense, Intercellular Signaling Peptides and Proteins
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